Secondary amino anilinic piperidines as mch1 antagonists and uses thereof

ABSTRACT

This invention is directed to compounds which are selective antagonists for melanin concentrating hormone-1 (MCH1) receptors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compounds of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject. This invention further provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound of the invention effective to treat the subject=s depression and/or anxiety. This invention further provides a method of treating a subject suffering from a urinary disorder.

This application claims priority of U.S. Ser. No. 10/189,145, filed Jul.3, 2002, the contents of which are hereby incorporated by reference.

Throughout this application, various publications are referenced inparentheses by author and year. Full citations for these references maybe found at the end of the specification immediately preceding theclaims.

The disclosure of these publications in their entireties are herebyincorporated by reference into this application to describe more fullythe state of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

Melanin-concentrating hormone (MCH) is a cyclic peptide originallyisolated from salmonid (teleost fish) pituitaries (Kawauchi et al.,1983). In fish the 17 amino acid peptide causes aggregation of melaninwithin the melanophores and inhibits the release of ACTH, acting as afunctional antagonist of α-MSH. Mammalian MCH (19 amino acids) is highlyconserved between rat, mouse, and human, exhibiting 100% amino acididentity, but its physiological roles are less clear. MCH has beenreported to participate in a variety of processes including feeding,water balance, energy metabolism, general arousal/attention state,memory and cognitive functions, and psychiatric disorders (for reviews,see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996). Itsrole in feeding or body weight regulation is supported by a recentNature publication (Qu et al., 1996) demonstrating that MCH isoverexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice,and that fasting further increased MCH mRNA in both obese and normalmice during fasting. MCH also stimulated feeding in normal rats wheninjected into the lateral ventricles (Rossi et al., 1997).

MCH also has been reported to functionally antagonize the behavioraleffects of α-MSH (Miller et al., 1993; Gonzalez et al, 1996; Sanchez etal., 1997); in addition, stress has been shown to increase POMC mRNAlevels while decreasing the MCH precursor preproMCH (ppMCH) mRNA levels(Presse et al., 1992). Thus MCH may serve as an integrative neuropeptideinvolved in the reaction to stress, as well as in the regulation offeeding and sexual activity (Baker, 1991; Knigge et al., 1996).

The biological effects of MCH are believed to be mediated by specificreceptors. A tritiated ligand ([³H]-MCH) was reported to exhibitspecific binding to brain membranes but was unusable for saturationanalyses, so neither affinity nor B_(max) were determined (Drozdz andEberle, 1995). Radioiodination of the tyrosine at position thirteenresulted in a ligand with dramatically reduced biological activity (seeDrozdz and Eberle, 1995). In contrast, the radioiodination of the MCHanalogue [Phe¹³,Tyr¹⁹]-MCH was successful (Drozdz et al., 1995); theligand retained biological activity and exhibited specific binding to avariety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7),PC12, and COS cells.

In G4F-7 cells, the K_(D)=0.118 nM and the B_(max) ˜1100 sites/cell.Importantly, the binding was not inhibited by α-MSH but was weaklyinhibited by rat ANF (Ki=116 nM vs. 12 nM for native MCH) (Drozdz etal., 1995). More recently specific MCH binding was reported intransformed keratinocytes (Burgaud et al., 1997) and melanoma cells(Drozdz et al., 1998), where photo-crosslinking studies suggest that thereceptor is a membrane protein with an apparent molecular weight of45-50 kDaltons, compatible with the molecular weight range of the GPCRsuperfamily of receptors. No radioautoradiographic studies of MCHreceptor localization using this ligand have been reported as yet.

The localization and biological activities of MCH peptide suggest thatthe modulation of MCH receptor activity may be useful in a number oftherapeutic applications. The role of MCH in feeding is the bestcharacterized of its potential clinical uses. MCH is expressed in thelateral hypothalamus, a brain area implicated in the regulation ofthirst and hunger (Grillon et al., 1997); recently orexins A and B,which are potent orexigenic agents, have been shown to have very similarlocalization to MCH in the lateral hypothalamus (Sakurai et al., 1998).MCH mRNA levels in this brain region are increased in rats after 24hours of food-deprivation (Hervé and Fellman, 1997); after insulininjection, a significant increase in the abundance and stainingintensity of MCH immunoreactive perikarya and fibres was observedconcurrent with a significant increase in the level of MCH mRNA(Bahjaoui-Bouhaddi et al., 1994).

Consistent with the ability of MCH to stimulate feeding in rats (Rossiet al., 1997) is the observation that MCH mRNA levels are upregulated inthe hypothalami of obese ob/ob mice (Qu et al., 1996), and decreased inthe hypothalami of rats treated with leptin, whose food intake and bodyweight gains are also decreased (Sahu, 1998). MCH appears to act as afunctional antagonist of the melanocortin system in its effects on foodintake and on hormone secretion within the HPA(hypothalamopituitary/adrenal axis) (Ludwig et al., 1998). Togetherthese data suggest a role for endogenous MCH in the regulation of energybalance and response to stress, and provide a rationale for thedevelopment of specific compounds acting at MCH receptors for use in thetreatment of obesity and stress-related disorders.

In all species studied to date, a major portion of the neurons of theMCH cell group occupies a rather constant location in those areas of thelateral hypothalamus and subthalamus where they lie and may be a part ofsome of the so-called “extrapyramidal” motor circuits. These involvesubstantial striato- and pallidofugal pathways involving the thalamusand cerebral cortex, hypothalamic areas, and reciprocal connections tosubthalamic nucleus, substantia nigra, and mid-brain centers(Bittencourt et al., 1992). In their location, the MCH cell group mayoffer a bridge or mechanism for expressing hypothalamic visceralactivity with appropriate and coordinated motor activity. Clinically itmay be of some value to consider the involvement of this MCH system inmovement disorders, such as Parkinson=s disease and Huntingdon's Choreain which extrapyramidal circuits are known to be involved.

Human genetic linkage studies have located authentic. hMCH loci onchromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5(5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with alocus to which autosomal dominant cerebellar ataxia type II (SCA2) hasbeen mapped (Auburger et al., 1992; Twells et al., 1992). This diseasecomprises neurodegenerative disorders, including an olivopontocerebellaratrophy.

Furthermore, the gene for Darier's disease, has been mapped to locus12q23-24 (Craddock et al., 1993). Darier's disease is characterized byabnormalities I keratinocyte adhesion and mental illnesses in somefamilies. In view of the functional and neuroanatomical patterns of theMCH neural system in the rat and human brains, the MCH gene mayrepresent a good candidate for SCA2 or Darier's disease. Interestingly,diseases with high social impact have been mapped to this locus. Indeed,the gene responsible for chronic or acute forms of spinal muscularatrophies has been assigned to chromosome 5q12-13 using genetic linkageanalysis (Melki et al., 1990; Westbrook et al., 1992). Furthermore,independent lines of evidence support the assignment of a majorschizophrenia locus to chromosome 5q11.2-13.3 (Sherrington et al., 1988;Bassett et al., 1988; Gilliam et al., 1989). The above studies suggestthat MCH may play a role in neurodegenerative diseases and disorders ofemotion.

Additional therapeutic applications' for MCH-related compounds aresuggested by the observed effects of MCH in other biological systems.For example, MCH may regulate reproductive functions in male and femalerats. MCH transcripts and MCH peptide were found within germ cells intestes of adult rats, suggesting that MCH may participate in stem cellrenewal and/or differentiation of early spermatocytes (Hervieu et al.,1996). MCH injected directly into the medial preoptic area (MPOA) orventromedial nucleus (VMN) stimulated sexual activity in female rats(Gonzalez et al., 1996). In ovariectomized rats primed with estradiol,MCH stimulated luteinizing hormone (LH) release while anti-MCH antiseruminhibited LH release (Gonzalez et al., 1997). The zona incerta, whichcontains a large population of MCH cell bodies, has previously beenidentified as a regulatory site for the pre-ovulatory LH surge(MacKenzie et al., 1984).

MCH has been reported to influence release of pituitary hormonesincluding ACTH and oxytocin. MCH analogues may also be useful intreating epilepsy. In the PTZ seizure model, injection of MCH prior toseizure induction prevented seizure activity in both rats and guineapigs, suggesting that MCH-containing neurons may participate in theneural circuitry underlying PTZ-induced seizure (Knigge and Wagner,1997). MCH has also been observed to affect behavioral correlates ofcognitive functions. MCH treatment hastened extinction of the passiveavoidance response in rats (McBride et al., 1994), raising thepossibility that MCH receptor antagonists may be beneficial for memorystorage and/or retention. A possible role for MCH in the modulation orperception of pain is supported by the dense innervation of theperiaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH mayparticipate in the regulation of fluid intake. ICV infusion of MCH inconscious sheep produced diuretic, natriuretic, and kaliuretic changesin response to increased plasma volume (Parkes, 1996). Together withanatomical data reporting the presence of MCH in fluid regulatory areasof the brain, the results indicate that MCH may be an important peptideinvolved in the central control of fluid homeostasis in mammals.

The identification of a G-protein coupled receptor for MCH has recentlybeen published (Chambers et al., 1999; Saito et al., 1999). These groupsidentified MCH as the endogenous ligand for the human orphan G-proteincoupled receptor SLC-1 (Lakaye et al., 1998). The rat homologue of thisreceptor (now called MCH-1) was reported to be localized in regions ofthe rat brain associated with feeding behavior (e.g. dorsomedial andventromedial hypothalamus). The link between MCH-1 and the effects ofMCH on feeding has been strengthened by recent reports on the phenotypeof MCH-1 knockout mice. Two groups have shown independently (Marsh etal, 2002; Chen et al, 2002) that the targeted disruption of the MCH-1receptor gene (MCH-1 knockout) in mice results in animals that arehyperphagic but are lean and have decreased body mass relative towild-type littermates. The decrease in body mass is attributed to anincrease in metabolism. Each group demonstrated that the MCH-1 knockoutmice are resistant to diet-induced obesity, and generally exhibitweights similar to littermates maintained on regular chow.

Finally, synthetic antagonist molecules for the MCH-1 receptor have nowbeen described in the literature. Bednarek et al. (2002) have reportedon the synthesis of high affinity peptide antagonists of MCH-1. Inaddition, a small molecule antagonist of MCH-1 has been described byTakekawa et al. (Takekawa et al., 2002). This compound, T-226296,exhibits high affinity for the MCH-1 receptor (˜5-9 nM for rat and humanMCH-1), and was shown to inhibit food intake induced by theintracerebroventricular application of MCH. These data validate thestrategy of using an MCH-1 receptor antagonist to treat obesity.

Furthermore, in our own studies, we have tested MCH1 antagonists inseveral animal models that are well known as predictive for the efficacyof compounds in humans (Borowsky, et al., Nature Medicine 2003). Theseexperiments indicate that MCH1 antagonists are useful to treat obesity,depression, anxiety, as well as urinary disorders.

Herein, we report the synthesis of secondary amino anilinic piperidinesthat bind to the cloned human melanin-concentrating hormone-1 (MCH1)receptor. Additionally, these compounds selectively bind to theMCH1-receptor against other cloned G-protein coupled receptor. Theability to inhibit the activation of the cloned receptor as measured inin vitro assays is disclosed.

Furthermore, the compounds of the present invention may also be used totreat abnormal conditions mediated by inactivation of the MCH-1 receptorsuch as feeding disorders (obesity, bulimia and bulimia nervosa),sexual/reproductive disorders, depression, anxiety, depression andanxiety, epileptic seizure, hypertension, cerebral hemorrhage,congestive heart failure, sleep disturbances, or any condition in whichantagonism of an MCH1 receptor may be beneficial.

In addition, the compounds of the present invention may be used toreduce the body mass of a subject. Furthermore, the compounds of thepresent invention may be used to treat urinary disorders.

SUMMARY OF THE INVENTION

This invention provides a compound having the structure:

wherein each A is independently —H, —F, —Cl, —Br, —I, —CN, —NO₂, —OR₃ orstraight chained or branched C₁-C₇ alkyl;wherein each B is independently N or CH;wherein Z is CO or SO₂;wherein each R is independently —H, —F or straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;wherein R₄ is independently —OR₃, —NHR₃, —SR₃, —COR₃, straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith one or more —F, —Cl, —Br, —I, —OR₂, or straight chained or branchedC₁-C₇ alkyl;wherein each R₃ is independently —H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; aryl or heteroaryl, whereinthe aryl or heteroaryl is optionally substituted with one or more —F,—Cl, —Br, —I, —NO₂, —CN, —OR₂, or —NHR₂;wherein each R₂ is independently —H, straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN; andwherein n is an integer from 1 to 6 inclusive;or a pharmaceutically acceptable salt thereof.

In a further embodiment of the aforementioned invention, the compound isenantiomerically and diasteriomerically pure. In another embodiment, thecompound is enantiomerically or diasteriomerically pure. In oneembodiment, the compound is a (+) enantiomer. In one embodiment, thecompound is a (−) enantiomer.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a therapeutically effectiveamount of any one the compounds of the invention.

An illustration of the invention is a pharmaceutical composition made byadmixing any one of the compounds described above and a pharmaceuticallyacceptable carrier.

Illustrative of the invention is a process for making a pharmaceuticalcomposition comprising admixing any of the compounds of the inventionand a pharmaceutically acceptable carrier.

Illustrative of the invention is a synthetic process for making any ofthe compounds of the invention.

Exemplifying the invention is a method of treating a disorder mediatedby the MCH1 receptor in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of anyone of the compounds or pharmaceutical compositions of the invention anda pharmaceutically acceptable carrier.

In one embodiment, the therapeutically effective amount is between about0.03 and about 300 mg.

In one embodiment, the disorder is depression. In one embodiment, thedisorder is anxiety. In one embodiment, the disorder is obesity. In oneembodiment, the disorder is urge incontinence.

One embodiment is a method of treating a subject suffering from adisorder selected from depression, anxiety, obesity or urge incontinencein a subject in need thereof, comprising administering to a subject atherapeutically effective amount of a compound of the invention.

In one embodiment, the therapeutically effective amount is between about0.03 and about 300 mg.

In another embodiment, the disorder is depression. In one embodiment,the disorder is anxiety. In one embodiment, the disorder is obesity. Inone embodiment, the disorder is urge incontinence.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a compound having the structure:

wherein each A is independently —H, —F, —Cl, —Br, —I, —CN, —NO₂, —OR₃ orstraight chained or branched C₁-C₇ alkyl;wherein each B is independently N or CH;wherein Z is CO or SO₂;wherein each R is independently —H, —F or straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;wherein R₄ is independently —OR₃, —NHR₃, —SR₃, —COR₃, straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith one or mote —F, —Cl, —Br, —I, —OR₂, or straight chained or branchedC₁-C₇ alkyl;wherein each R₃ is independently —H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; aryl or heteroaryl, whereinthe aryl or heteroaryl is optionally substituted with one or more —F,—Cl, —Br, —I, —NO₂, —CN, —OR₂, or —NHR₂;wherein each R₂ is independently —H, straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN; andwherein n is an integer from 1 to 6 inclusive;or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound has the structure:

In one embodiment the compound has the structure:

wherein R₄ is aryl or heteroaryl, wherein the aryl or heteroaryl isoptionally substituted with one or more —F, —Cl, —Br, —I, —OR₃, orstraight chained or branched C₁-C₇ alkyl;wherein each R₃ is straight chained or branched C₁-C₇ alkyl, aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith one or more —F, —Cl, —Br, —I, —NO₂, —CN, or —OR₂; andwherein each R₂ is —H, straight chained or branched C₁-C₇ alkyl, aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith one or more —F, —Cl, —Br, —I, —NO₂, —CN.

In one embodiment of the invention is the compound having the structure:

wherein R₂ is —H, straight chained or branched C₁-C₇ alkyl, or arylwherein the aryl is optionally substituted with one or more —F, —Cl,—Br, —I, —NO₂, or —CN.

In one embodiment the compound has the structure:

wherein R₂ is straight chained or branched C₁-C₇ alkyl; andwherein n is an integer from 3-6 inclusive.

The compound of the invention wherein the compound has the structure:

wherein each A is independently —H, —F, —Cl, —Br or —I.

In one embodiment, the compound has the structure:

wherein each A is independently —H, —F or —Cl; andwherein R₂ is straight chained or branched C₁-C₃ alkyl.

The compound having the structure:

The compound having the structure:

In one embodiment the compound has the structure:

wherein R₂ is aryl, wherein the aryl is optionally substituted with oneor more —F, —Cl, —Br, —I, —NO₂, or —CN; andwherein n is an integer from 1 to 6 inclusive;

In one embodiment the compound has the structure:

wherein each A is independently —H, —F, —Cl, —Br or —I.

In one embodiment the compound has the structure:

wherein each A is independently —H, —F or —Cl; and wherein R₂ is aryloptionally substituted with one or more —F, —Cl, or —Br.

In one embodiment the compound has the structure:

wherein each A is independently —H, —F or —Cl; andwherein R₂ is aryl optionally substituted with one or more —F.

In one embodiment the compound has the structure:

In one embodiment the compound has the structure:

In one embodiment the compound has the structure:

wherein R₄ is aryl optionally substituted with one or more —F, —Cl, —Br,—I, —OR₃, or straight chained or branched C₁-C₇ alkyl;wherein each R₃ is independently straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN, or —OR₂;wherein each R₂ is independently straight chained or branched C₁-C₇alkyl.

This invention further provides a compound having the structure:

wherein R₄ is independently —OR₃, —NHR₃, —COR₃ or —SR₃;wherein each R₃ is independently straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN, —OR₂, or—NHR₂;wherein R₂ is —H, straight chained or branched C₁-C₇ alkyl, or arylwherein the aryl is optionally substituted with one or more —F, —Cl,—Br, —I, —NO₂, —CN; andwherein n is an integer from 1 to 6 inclusive;

In one embodiment the compound has the structure:

wherein each A is independently —H, —F, —Cl, —Br or —I;wherein R₄ is independently —OR₃, —NHR₃, or —COR₃;wherein R₃ is aryl optionally substituted with one or more —F, —Cl, —Br,—I, —NO₂, —CN, —OR₂ or —NHR₂;wherein each R₂ is independently —H, straight chained or branched C₁-C₇alkyl or aryl optionally substituted with one or more —F, —Cl, —Br, —I,—NO₂, —CN; andwherein n is an integer from 1 to 6 inclusive.

In one embodiment the compound has the structure:

wherein each A is independently —H or —F;wherein R₃ is aryl optionally substituted with one or more —F, —Cl, —Br,—I, —NO₂, —CN, —OR₂ or —NHR₂;wherein R₂ is independently straight chained or branched C₁-C₇ alkyl oraryl optionally substituted with one or more —F, —Cl, —Br or —I; andwherein n is an integer from 1 to 6 inclusive.

In one embodiment of the invention, the compound has the structure:

wherein A is —H, —F, —Cl, —Br or —I;wherein aryl optionally substituted with one or more —F, —Cl, —Br, —I;

The compound having the structure:

In one embodiment the compound has the structure:

In one embodiment the compound has the structure:

wherein A is —H, —F, —Cl, —Br or —I;wherein R₃ is aryl optionally substituted with one or more —F, —Cl, —Bror —I.

The compound having the structure:

The compound having the structure:

This invention also provides a compound having the structure:

wherein each Q independently is hydrogen;

wherein X is aryl or heteroaryl, wherein the aryl or heteroaryl isoptionally substituted with one or more —F, —Cl, —Br, —I, -ZR₃, -ZOR₃,—OZR₃, -ZN(R₃)₂, —N(R₃)ZR₃, N(R₃)ZN(R₃)₂, —CN, —NO₂, —SR₃,—(CH₂)_(q)OR₃, —(CH₂)_(q)SR₃, aryl, phenoxy or heteroaryl, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl or C₃-C₇cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;wherein each Z is independently CO; CS; SO₂; or null;wherein each R is independently —H; —F; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; —N(R₃)₂; —NO₂; —CN; —CO₂R₃; —OCOR₃;—OR₃; N(R₃)COR₃ or —CON(R₃)₂;wherein each R₂ is independently —H, straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, orstraight chained or branched C₂-C₇ alkenyl or alkynyl;wherein each R₃ is independently —H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branchedC₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; aryl or heteroaryl, wherein thearyl or heteroaryl is optionally substituted with one or more —F, —Cl,—Br, —I, —N(R₂)₂, —NO₂, —CN, —COR₂—CO₂R₂, —OCOR₂,—OR₂₁—N(R₂)COR₂—N(R₂)CON(R₂)₂, —CON(R₂)₂, aryl, heteroaryl, phenoxy,straight chained or branched C₁-C₇ alkyl, monofluoroalkyl orpolyfluoroalkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl,C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl orcycloalkenyl;wherein each R₄ is independently —H; -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂,—N(R₃)ZR₃, —N(R₃)ZN(R₃)₂, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, aryl, benzyl or heteroaryl, whereinthe aryl, benzyl or heteroaryl is optionally substituted with one ormore —F, —Cl, —Br, —I, -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂, —N(R₃)ZR₃,—N(R₃)ZN(R₃)₂, —CN, —NO₂, —SR₃, —(CH₂)_(q)OR₃, —(CH₂)_(q)SR₃, aryl,benzyl, heteroaryl, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl or alkynyl or C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl, or cycloalkenyl;wherein each k is independently an integer from 1 to 3 inclusive;wherein each m is independently an integer from 0 to 1 inclusive;wherein n is an integer from 0 to 6 inclusive;wherein q is an integer from 1 to 3 inclusive;or a pharmaceutically acceptable salt thereof.

This invention also provides a compound having the structure:

wherein each Q is independently hydrogen;

wherein X is aryl or heteroaryl, wherein the aryl or heteroaryl isoptionally substituted with one or more —F, —Cl, —Br, —I, -ZR₃, -ZOR₃,—OZR₃, -ZN(R₃)₂, —N(R₃)ZR₃, —N(R₃)ZN(R₃)₂, —CN, —NO₂, —SR₃,—(CH₂)_(q)OR₃, —(CH₂)_(q)SR₃, aryl, phenoxy or heteroaryl, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl or C₃-C₇cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;wherein each Z is independently CO; CS; SO₂; or null;wherein each R is independently —H; —F; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; —N(R₃)₂; —NO₂; —CN; —CO₂R₃; —OCOR₃;—OR₃; —N(R₃)COR₃ or —CON(R₃)₂;wherein each R₂ is independently —H, straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more F, —Cl, —Br, —I, —NO₂, —CN, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, orstraight chained or branched C₂-C₇ alkenyl or alkynyl;wherein each R₃ is independently —H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branchedC₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; aryl or heteroaryl, wherein thearyl or heteroaryl is optionally substituted with one or more —F, —Cl,—Br, —I, —N(R₂)₂, —NO₂, —CN, —COR₂—CO₂R₂, —OCOR₂, —OR₂,—N(R₂)COR₂—N(R₂)CON(R₂)₂, —CON(R₂)₂, aryl, heteroaryl, phenoxy, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;wherein each R₄ is independently —H; -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂,—N(R₃)ZR₃, —N(R₃)ZN(R₃)₂, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, aryl, benzyl or heteroaryl, whereinthe aryl, benzyl or heteroaryl is optionally substituted with one ormore —F, —Cl, —Br, —I, -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂, —N(R₃)ZR₃,N(R₃)ZN(R₃)₂, —CN, —NO₂, —SR₃, —(CH₂)_(q)OR₃, —(CH₂)_(q)SR₃, aryl,benzyl, heteroaryl, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl or alkynyl or C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl, or cycloalkenyl;wherein each k is independently an integer from 1 to 3 inclusive;wherein n is an integer from 0 to 6 inclusive;wherein q is an integer from 1 to 3 inclusive;or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a pharmaceuticallytherapeutically effective amount of any one the compounds describedabove.

An illustration of the invention is a pharmaceutical composition made byadmixing any one of the compounds described above and a pharmaceuticallyacceptable carrier.

Illustrative of the invention is a process for making a pharmaceuticalcomposition comprising admixing any of the compounds described above anda pharmaceutically acceptable carrier.

Illustrative of the invention is a synthetic process for making any ofthe compounds described above.

Exemplifying the invention is a method of treating a condition mediatedby the MCH1 receptor in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of anyone of the compounds or pharmaceutical compositions described above anda pharmaceutically acceptable carrier.

This invention also provides a compound having the structure:

wherein each Q is independently hydrogen;

wherein X is phenyl or a nitrogen containing hetercycle, wherein thephenyl or a nitrogen containing hetercycle is optionally substitutedwith one or more —F, —Cl, —Br, —I, -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂,—N(R₃)ZR₃, —N(R₃)ZN(R₃)₂, —CN, —NO₂, —SR₃, —(CH₂)_(q)OR₃, —(CH₂)_(q)SR₃,aryl, phenoxy or heteroaryl, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl or alkynyl or C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl;wherein each Z is independently CO; CS; SO₂; or null;wherein each R is independently —H; —F; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; —N(R₃)₂; —NO₂; —CN; —CO₂R₃; —OCOR₃;—OR₃; —N(R₃)COR₃ or —CON(R₃)₂;wherein each R₂ is independently —H, straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, orstraight chained or branched C₂-C₇ alkenyl or alkynyl;wherein each R₃ is independently —H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branchedC₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; aryl or heteroaryl, wherein thearyl or heteroaryl is optionally substituted with one or more —F, —Cl,—Br, —I, —N(R₂)₂, —NO₂, —CN, —COR₂—CO₂R₂, —OCOR₂, —OR₂,—N(R₂)COR₂—N(R₂)CON(R₂)₂, —CON(R₂)₂, aryl, heteroaryl, phenoxy, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;wherein each R₄ is independently —H; -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂,—N(R₃)ZR₃, —N(R₃)ZN(R₃)₂, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, aryl, benzyl or heteroaryl, whereinthe aryl, benzyl or heteroaryl is optionally substituted with one ormore —F, —Cl, —Br, —I, -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂, —N(R₃)ZR₃,—N(R₃)ZN(R₃)₂, —CN, —NO₂, —SR₃, —(CH₂)_(q)OR₃, —(CH₂)_(q)SR₃, aryl,benzyl, heteroaryl, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl or alkynyl or C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl, or cycloalkenyl;wherein each k is independently an integer from 1 to 3 inclusive;wherein n is an integer from 0 to 6 inclusive;wherein q is an integer from 1 to 3 inclusive;or a pharmaceutically acceptable salt thereof.

This invention provides a compound having the structure:

wherein each Q is independently hydrogen;

wherein each A is independently —H, —F, —Cl, —Br, —I, -ZR₃, -ZOR₃,—OZR₃, -ZN(R₃)₂, —N(R₃)ZR₃, —N(R₃)ZN(R₃)₂, —CN, —NO₂, —N(R₃)₂, —OR₃,—SR₃, —(CH₂)_(q)OR₃, —(CH₂)_(q)SR3, straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl, or cycloalkenyl;wherein each B is independently N or CH;wherein each Z is independently CO; CS; SO₂ or null;wherein each R is independently —H, —F, straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, —N(R₃)₂, —NO₂, —CN, —CO₂R₃, —OCOR₃,—OR₃, —N(R₃)COR₃ or —CON(R₃)₂;wherein each R₂ is independently —H, straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, orstraight chained or branched C₂-C₇ alkenyl or alkynyl;wherein each R₃ is independently —H; straight chained or branched C₁-C₇alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branchedC₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl; aryl or heteroaryl, wherein thearyl or heteroaryl is optionally substituted with one or more —F, —Cl,—Br, —I, —N(R₂)₂, —NO₂, —CN, —COR₂—CO₂R₂, —OCOR₂, —OR₂,—N(R₂)COR₂—N(R₂)CON(R₂)₂, —CON(R₂)₂, aryl, heteroaryl, phenoxy, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl,straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl,monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;wherein each R₄ is independently —H; -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂,—N(R₃)ZR₃, —N(R₃)ZN(R₃)₂, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, aryl, benzyl or heteroaryl, whereinthe aryl, benzyl or heteroaryl is optionally substituted with one ormore —F, —Cl, —Br, —I, -ZR₃, -ZOR₃, —OZR₃, -ZN(R₃)₂, —N(R₃)ZR₃,—N(R₃)ZN(R₃)₂, —CN, —NO₂, —SR₃, —(CH₂)_(q)OR₃, —(CH₂)_(q)SR₃, aryl,benzyl, heteroaryl, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl or alkynyl or C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl, or cycloalkenyl;wherein each k is independently an integer from 1 to 3 inclusive;wherein n is an integer from 0 to 6 inclusive;wherein q is an integer from 1 to 3 inclusive;or a pharmaceutically acceptable salt thereof.

In one embodiment, each A is independently —H, —F, —Cl, —Br, —I, -ZR₃,-ZOR₃, —OZR₃, -ZN(R₃)₂, —N(R₃)ZR₃, —N(R₃)ZN(R₃)₂, —N(R₃)₂, —OR₃, —SR₃,—(CH₂)_(q)OR₃, —(CH₂)_(q)SR₃, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl;

wherein each Z is independently CO; CS or null;

wherein each R is independently —H, —F or straight chained or branchedC₁-C₇ alkyl;

wherein each R₂ is independently —H, straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN, straightchained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl, orstraight chained or branched C₂-C₇ alkenyl or alkynyl;

wherein each R₃ is independently —H, straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —N(R₂)₂, —NO₂, —CN,—COR₂—CO₂R₂, —OCOR₂, —OR₂, —N(R₂)COR₂—N(R₂)CON(R₂)₂, —CON(R₂)₂, aryl,heteroaryl, phenoxy, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl or cycloalkenyl;

In one embodiment, the compound has the structure:

In one embodiment, the compound has the structure:

In one embodiment, the compound has the structure:

In one embodiment, the compound has the structure:

wherein R₄ is aryl, wherein the aryl is optionally substituted with oneor more —F, —Cl, —Br, —I, straight chained or branched C₃-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl or alkynyl or C₃-C₇ cycloalkyl, monofluorocycloalkyl,polyfluorocycloalkyl, or cycloalkenyl.

In one embodiment, the compound has the structure:

In one embodiment, the compound has the structure:

In one embodiment, the compound has the structure:

wherein R₃ is aryl or heteroaryl, wherein the aryl or heteroaryl isoptionally substituted with one or more —F, —Cl, —Br, —I, —N(R₂)₂, —NO₂,—CN, —COR₂—CO₂R₂, —OCOR₂, —OR₂, —N(R₂)COR₂—N(R₂)CON(R₂)₂, —CON(R₂)₂,aryl, heteroaryl, phenoxy, straight chained or branched C₁-C₇ alkyl.

In one embodiment, the compound has the structure:

In one embodiment, the compound has the structure:

As used in the above-described inventions, the term “heteroaryl” is usedto include five and six membered unsaturated rings that may contain oneor more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groupsinclude, but are not limited to, carbazole, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, and triazinyl.

In addition, the term “heteroaryl” is used to include fused bicyclicring systems that may contain one or more heteroatoms such as oxygen,sulfur and nitrogen. Examples of such heteroaryl groups include, but arenot limited to, indolizinyl, indolyl, isoindolyl, benzo[b]furanyl,benzo[b]thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl,benzisoxazolyl, benzo[b]thiazolyl, imidazo[2,1-b]thiazolyl, cinnolinyl,quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, phthalimidyl and 2,1,3-benzothiazolyl.

The term “heteroaryl” also includes those chemical moieties recitedabove which may be substituted with one or more of the following: —F,—Cl, —Br, —I, CN, —NO₂, straight chained or branched C₁-C₇ alkyl,straight chained or branched C₁-C₇ monofluoroalkyl, straight chained orbranched C₁-C₇ polyfluoroalkyl, straight chained or branched C₂-C₇alkenyl, straight chained or branched C₂-C₇ alkynyl; C₃-C₇ cycloalkyl,C₃-C₇ monofluorocycloalkyl, C₃-C₇ polyfluorocycloalkyl, C₅-C₇cycloalkenyl,

The term “heteroaryl” further includes the N-oxides of those chemicalmoieties recited above which include at least one nitrogen atom. In thepresent invention, the term “aryl” is phenyl or naphthyl.

In a further embodiment of the aforementioned invention, the compound isenantiomerically and diasteriomerically pure. In another embodiment, thecompound is enantiomerically or diasteriomerically pure.

In one embodiment, the compound is a (+) enantiomer. In one embodiment,the compound is a (−) enantiomer.

The invention provides for each pure stereoisomer of any of thecompounds described herein. Such stereoisomers may include enantiomers,diastereomers, or E or Z alkene or imine isomers. The invention alsoprovides for stereoisomeric mixtures, including racemic mixtures,diastereomeric mixtures, or E/Z isomeric mixtures. Stereoisomers can besynthesized in pure form (Nógrádi, M.; Stereoselective Synthesis, (1987)VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 B 5, (1983)Academic Press, Editor Morrison, J.) or they can be resolved by avariety of methods such as crystallization and chromatographictechniques (Jaques, J.; Collet, A.; Wilen, S.; Enantiomer, Racemates,and Resolutions, 1981, John Wiley and Sons and Asymmetric Synthesis,Vol. 2, 1983, Academic Press, Editor Morrison, J).

In addition the compounds of the present invention may be present asenantiomers, diasteriomers, isomers or two or more of the compounds maybe present to form a racemic or diastereomeric mixture.

The compounds of the present invention are preferably 80% pure, morepreferably 90% pure, and most preferably 95% pure. Included in thisinvention are pharmaceutically acceptable salts and complexes of all ofthe compounds described herein. The acids and bases from which thesesalts are prepared include but are not limited to the acids and baseslisted herein. The acids include, but are not limited to, the followinginorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid and boric acid. The acids include, but are not limited to,the following organic acids: acetic acid, malonic acid, succinic acid,fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonicacid, benzoic acid, glycolic acid, lactic acid and mandelic acid. Thebases include, but are not limited to ammonia, methylamine, ethylamine,propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine,ethylenediamine, hydroxyethylamine, morpholine, piperazine andguanidine. This invention further provides for the hydrates andpolymorphs of all of the compounds described herein.

The present invention includes within its scope prodrugs of thecompounds of the invention. In general, such prodrugs will be functionalderivatives of the compounds of the invention which are readilyconvertible in vivo into the required compound. Thus, in the presentinvention, the term “administering” shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in Design ofProdrugs, ed. H. Bundgaard, Elsevier, 1985.

The present invention further includes metabolites of the compounds ofthe present invention. Metabolites include active species produced uponintroduction of compounds of this invention into the biological milieu.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a therapeutically effectiveamount of any one the compounds of the invention.

An illustration of the invention is a pharmaceutical composition made byadmixing any one of the compounds described above and a pharmaceuticallyacceptable carrier.

Illustrative of the invention is a process for making a pharmaceuticalcomposition comprising admixing any of the compounds of the inventionand a pharmaceutically acceptable carrier.

A solid carrier can include one or more substances which may also act asendogenous carriers (e.g. nutrient or micronutrient carriers), flavoringagents, lubricants, solubilizers, suspending agents, fillers, glidants,compression aids, binders or tablet-disintegrating agents; it can alsobe an encapsulating material. In powders, the carrier is a finelydivided solid which is in admixture with the finely divided activeingredient. In tablets, the active ingredient is mixed with a carrierhaving the necessary compression properties in suitable proportions andcompacted in the shape and size desired. The powders and tabletspreferably contain up to 99% of the active ingredient. Suitable solidcarriers include, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, coloring agents, viscosityregulators, stabilizers or osmoregulators. Suitable examples of liquidcarriers for oral and parenteral administration include water (partiallycontaining additives as above, e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate or isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be a halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular, intrathecal,epidural, intraperitoneal or subcutaneous injection. Sterile solutionscan also be administered intravenously. The compounds may be prepared asa sterile solid composition which may be dissolved or suspended at thetime of administration using sterile water, saline, or other appropriatesterile injectable medium. Carriers are intended to include necessaryand inert binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. The compound can beadministered orally in the form of a sterile solution or suspensioncontaining other solutes or suspending agents (for example, enoughsaline or glucose to make the solution isotonic), bile salts, acacia,gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitoland its anhydrides copolymerized with ethylene oxide) and the like.

The compound can also be administered orally either in liquid or solidcomposition form. Compositions suitable for oral administration includesolid forms, such as pills, capsules, granules, tablets, and powders,and liquid forms, such as solutions, syrups, elixirs, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions, and suspenions.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated will result in a need to adjust dosages, includingsubject age, weight, gender, diet, and time of administration.

Illustrative of the invention is a synthetic process for making any ofthe compounds of the invention.

Exemplifying the invention is a method of treating a disorder mediatedby the MCH1 receptor in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of anyone of the compounds or pharmaceutical compositions of the invention anda pharmaceutically acceptable carrier.

In one embodiment, the therapeutically effective amount is between about0.03 and about 300 mg.

In one embodiment, the disorder is depression. In one embodiment, thedisorder is anxiety. In one embodiment, the disorder is obesity. In oneembodiment, the disorder is urge incontinence.

One embodiment is a method of treating a subject suffering from adisorder selected from depression, anxiety, obesity or urge incontinencein a subject in need thereof, comprising administering to a subject atherapeutically effective amount of a compound of the invention.

In one embodiment, the therapeutically effective amount is between about0.03 and about 300 mg.

In another embodiment, the disorder is depression. In one embodiment,the disorder is anxiety. In one embodiment, the disorder is obesity. Inone embodiment, the disorder is urge incontinence.

In the subject application a “therapeutically effective amount” is anyamount of a compound which, when administered to a subject sufferingfrom a disease against which the compounds are effective, causesreduction, remission, or regression of the disease. In a subjectapplication, a “subject” is a vertebrate, a mammal or a human.

This invention provides a method of treating a subject suffering from anabnormality wherein the abnormality is alleviated by decreasing theactivity of an MCH1 receptor which comprises administering to thesubject an amount of a compound of the invention which is an MCH1receptor antagonist effective to treat the subject's abnormality.

In separate embodiments, the abnormality is a regulation of a steroid orpituitary hormone disorder, an epinephrine release disorder, agastrointestinal disorder, a cardiovascular disorder, an electrolytebalance disorder, hypertension, diabetes, a respiratory disorder,asthma, a reproductive function disorder, an immune disorder, anendocrine disorder, a musculoskeletal disorder, a neuroendocrinedisorder, a cognitive disorder, a memory disorder such as Alzheimer-sdisease, a sensory modulation and transmission disorder, a motorcoordination disorder, a sensory integration disorder, a motorintegration disorder, a dopaminergic function disorder such asParkinson=s disease, a sensory transmission disorder, an olfactiondisorder, a sympathetic innervation disorder, an affective disorder suchas depression and anxiety, a stress-related disorder, a fluid-balancedisorder, a seizure disorder, pain, psychotic behavior such asschizophrenia, morphine tolerance, opiate addiction, migraine or aurinary disorder such as urinary incontinence.

In a preferred embodiment, the subject invention provides a method oftreatment for the following indications: depression, anxiety,eating/body weight disorders, and urinary disorders. Examples ofeating/body weight disorders are obesity, bulimia, or bulimia nervosa.Examples of urinary disorders include, but are not limited to, urinaryincontinence, overactive bladder, urge incontinence, urinary frequency,urinary urgency, nocturia, or enuresis. Overactive bladder and urinaryurgency may or may not be associated with benign prostatic hyperplasia.

This invention provides a method of modifying the feeding behavior of asubject which comprises administering to the subject an amount of acompound of the invention effective to decrease the consumption of foodby the subject.

This invention also provides a method of treating an eating disorder ina subject which comprises administering to the subject an amount of acompound of this invention effective to decrease the consumption of foodby the subject. In an embodiment of the present invention, the eatingdisorder is bulimia, obesity or bulimia nervosa. In an embodiment of thepresent invention, the subject is a vertebrate, a mammal, a human or acanine. In a further embodiment, the compound is administered incombination with food.

The present invention further provides a method of reducing the bodymass of a subject which comprises administering to the subject an amountof a compound of the invention effective to reduce the body mass of thesubject.

The present invention also provides a method of treating a subjectsuffering from depression which comprises administering to the subjectan amount of a compound of this invention effective to treat thesubject's depression. The present invention further provides a method oftreating a subject suffering from anxiety which comprises administeringto the subject an amount of a compound of this invention effective totreat the subject's anxiety. The present invention also provides amethod of treating a subject suffering from depression and anxiety whichcomprises administering to the subject an amount of a compound of thisinvention effective to treat the subject=s depression and anxiety.

The present invention also provides a method of treating a subjectsuffering from major depressive disorder, dysthymic disorder, bipolar Iand II disorders, schizoaffective disorder, cognitive disorders withdepressed mood, personality disorders, insomnia, hypersomnia,narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleepterror disorder, sleepwalking disorder, obsessive-compulsive disorder,panic disorder, with or without agoraphobia, posttraumatic stressdisorder, social anxiety disorder, social phobia and generalized anxietydisorder.

The present invention also provides a method of treating a subjectsuffering from a urinary disorder which comprises administering to thesubject an amount of a compound of this invention effective to treat thesubject's a urinary disorder. In some embodiments, the urinary disorderis urinary incontinence, overactive bladder, urge incontinence, urinaryfrequency, urinary urgency, nocturia, or enuresis.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

Experimental Section

I. Synthesis of Chemical Compounds

General Methods: All reactions were performed under an Argon atmosphereand the reagents, neat or in appropriate solvents, were transferred tothe reaction vessel via syringe and cannula techniques. The parallelsynthesis reaction arrays were performed in vials (without an inertatmosphere) using J-KEM heating shakers (Saint Louis, Mo.). Anhydroussolvents were purchased from Aldrich Chemical Company (Milwaukee, Wis.)and used as received.

Unless otherwise noted, the ¹H spectra were recorded at 400 MHz (Brüker,Model: Avance) with tetramethylsilane as internal standard. s=singlet;d=doublet; t=triplet; q=quartet; p=quintet; sextet; septet; br=broad;m=multiplet.

Elemental analyses were performed by Robertson Microlit Laboratories,Inc. Unless otherwise noted, mass spectra were obtained on a VG PatformII instrument using electrospray (ESI-MS) and MH⁺ is reported.Thin-layer chromatography (TLC) was carried out on glass platesprecoated with silica gel 60 F₂₅₄ (0.25 mm, EM Separations Tech.).Preparative thin-layer chromatography was carried out on glass sheetsprecoated with silica gel GF (2 mm, Analtech). Flash columnchromatography was performed on Merck silica gel 60 (230-400 mesh).Melting points (mp) were determined in open capillary tubes on aMeI-Temp apparatus and are uncorrected.The Following Schemes are Illustrative of Methods for SynthesizingCompounds of this Invention.

(a) LDA/PhNTf₂/THF/−78° C. then 0° C. overnight. (b) Aminophenylboronicacid/Pd(PPh)₄/LiCl/Na₂CO₃/DME-H₂O/reflux 3 h. (c) 10% Pd/C/H₂/EtOH/rt24-48 h. (d) Acid chloride/triethylamine/THF/0° C. then rt 2-3 h orCarboxylic acid/EDC/DMAP/CH₂Cl₂/DMF/rt 12 h. (e) 4M HCl in1,4-dioxane/rt 1 h or TFA/CH₂Cl₂/rt 10 min.

(a) Bis(pinacolato)diboron/KOAc/PdCl₂dppf/dppf/80° C. overnight. (b)K₂CO₃/PdCl₂dppf/DMF/80° C. overnight. (c) 10% Pd/C/H₂/EtOH/rt 24 h-72 h.(d) 4M HCl in 1,4-dioxane/rt 1 h or TFA/CH₂Cl₂/rt 10 min. (e) Carboxylicacid/EDC/DMAP/CH₂Cl₂/DMF/rt 12 h. (f) H₂SO₄/HNO₃, 0° C., 10 min. (g)Fe/NH₄Cl/THF/H₂O/EtOH/95° C., 1.5 h. (h) Cbz-Cl/NaHCO₃/CH₃CN/rt 12 h

(b) K₂CO₃/PdCl₂dppf/DMF/85° C. 24 h. (c) 10% Pd/C/H₂ (200psi)/EtOAc/MeOH/rt 24 h-72 h. (d) 4M HCl in 1,4-dioxane/rt 1 h orTFA/CH₂Cl₂/rt 0.2 h. (e) Carboxylic acid/EDC/DMAP/CH₂Cl₂/DMF/rt 12 h.General Procedure for Piperidine Synthesis (Scheme 1)

TERT-BUTYL 4-{[(TRIFLUOROMETHYL)SULFONYL]OXY}-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE

n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to asolution of diisopropylamine (96.2 mL, 44.2 mmol) in anhydrous THF (40.0mL) at 0° C. and the resulting mixture was stirred for 20 minutes. Thereaction mixture was cooled to −78° C. and tert-butyl4-oxo-1-piperidinecarboxylate (Aldrich Chemical Company, 7.97 g, 40.0mmol) in THF (40.0 mL) was added dropwise to the reaction mixture, whichwas then stirred for 30 minutes. Tf₂NPh (42.0 mmol, 15.0 g) in THF (40.0mL) was added dropwise to the reaction mixture and the reaction mixturewas stirred at 0° C. overnight. The reaction mixture was concentrated invacuo, redissolved in hexanes:EtOAc (9:1), passed through a plug ofalumina and the alumina plug was washed with hexanes:EtOAc (9:1). Thecombined extracts were concentrated in vacuo to yield the desiredproduct (16.5 g) which was contaminated with some starting materialTf₂N-Ph: ¹H NMR (400 MHz, CDCl₃) δ 5.77 (s, 1H), 4.05 (dm, 2H, J=3.0Hz), 3.63 (t, 2H, J=5.7 Hz), 2.45 (m, 2H), 1.47 (s, 9H).

TERT-BUTYL 4-(3-AMINOPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINE CARBOXYLATE

A degassed mixture of 2.0 M aqueous Na₂CO₃ solution (4.20 mL),tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridine carboxylate (0.500 g, 1.51mmol), 3-aminophenylboronic acid hemisulfate (0.393 g, 2.11 mmol),lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphinepalladium (0.080 g, 0.075 mmol) in dimethoxyethane (5.00 mL) was heatedat reflux temperature for 3 hours under Argon. The organic layer of thecooled reaction mixture was separated and the aqueous layer was washedwith ethyl acetate (3×50 mL). The combined organic solutions were driedand concentrated in vacuo. The crude product was chromatographed(silica, hexanes:EtOAc: dichloromethane 6:1:1 with 1% isopropylamine) togive the desired product (0.330 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 7.12(t, 1H, J=7.60 Hz), 6.78 (d, 1H, J=8.4 Hz), 6.69 (t, 1H, J=2.0 Hz), 6.59(dd, 1H, J=2.2, 8.0 Hz), 6.01 (br, 1H), 4.10-4.01 (d, 2H, J=2.4 Hz),3.61 (t, 2H, J=5.6 Hz), 2.52-2.46 (m, 2H), 1.49 (s, 9H); ESMS m/e: 275.2(M+H)⁺.

Anal. Calc. for C₁₆H₂₄N₂O₂: C, 70.04; H, 8.08; N, 10.21. Found: C,69.78; H, 7.80; N, 9.92.

TERT-BUTYL 4-[3-(AMINO)PHENYL]-1-PIPERIDINECARBOXYLATE

A mixture of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.10 g, 11.3 mmol) and 10% Pd/C (1.00 g) inethanol (100 mL) was hydrogenated at room temperature using the balloonmethod for 2 days. The reaction mixture was filtered through Celite andwashed with ethanol. The combined ethanol extracts were concentrated invacuo and the residue was chromatographed on silica (dichloromethane:methanol:isopropylamine 95:5:1) to give the desired product (2.63 g,84%). ¹H NMR (400 MHz, CDCl₃) δ 7.10 (t, 1H, J=7.6 Hz), 6.62 (d, 1H,J=8.4 Hz), 6.60-6.59 (m, 2H), 4.27-4.18 (m, 2H), 3.62-3.58 (m, 2H),2.80-2.72 (m, 2H), 2.62-2.59 (m, 1H), 1.89-1.52 (m, 4H), 1.49 (s, 9H);ESMS m/e: 277.2 (M+H)⁺.

TERT-BUTYL 4-{3-[(6-BROMOHEXANOYL)AMINO]PHENYL}-1-PIPERIDINE CARBOXYLATE

A 25-mL RB-flask, charged withtert-butyl-4-[3-(amino)phenyl]-1-piperidinecarboxylate (2.00 mmol, 0.553g), 6-bromohexanoyl chloride (0.427 g, 2.00 mmol, 1.0 eq.),triethylamine (0.404 g, 4.00 mmol) and THF (8.00 mL) was stirred at roomtemperature for 4 h. The reaction mixture was diluted with chloroform(50 mL) and washed with water (100 mL), brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by chromatography(silica gel, hexanes/EtOAc 10:1) to yield the desired product (0.921 g,95.8%). ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.28-7.22 (m, 2H), 7.11(s, 1H), 6.5 (d, 1H, J=7.0 Hz), 3.45-3.39 (m, 2H), 2.85-2.70 (m, 2H),2.68-2.58 (m, 1H), 2.37 (t, 2H, J=7.4 Hz), 1.96-1.71 (m, 7H), 1.68-1.50(m, 5H), 1.48 (s, 9H); ESMS m/e: 355.4, 476.6.

TERT-BUTYL4-(3-{[6-(3,4-DIFLUOROANILINO)HEXANOYL]AMINO}PHENYL)-1-PIPERIDINECARBOXYLATE

A 5-mL RB flask charged withtert-butyl-4-{3-[(6-bromohexanoyl)amino]phenyl}-1-piperidine carboxylate(40.9 mg, 0.100 mmol) 3,4-difluoroaniline (0.100 mmol, 12.9 mg), K₂CO₃(0.100 mmol, 13.8 mg), NaI (22.5 mg, 0.150 mmol) and DMF (1.00 mL) washeated at 120° C. for 12 hours. The mixture was diluted with water (10mL). The aqueous layer was extracted with chloroform (3×10 mL) and thecombined extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by chromatography(hexanes/EtOAc 10:1) to afford the desired product as a light yellow oil(7.14 mg, 14.3%). ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.31-7.18 (m,1H), 6.98-6.90 (m, 3H), 6.50-6.43 (m, 1H), 6.40-6.30 (m, 2H), 6.26-6.20(m, 1H), 4.28-4.18 (m, 2H), 3.06 (t, 2H, J=7.2 Hz), 2.97-2.87 (m, 1H),2.84-2.72 (m, 2H), 2.68-2.58 (m, 2H), 2.38 (t, 2H, J=7.4 Hz), 1.85-1.73(m, 4H), 1.7-1.54 (m, 4H), 1.48 (s, 9H); ESMS m/e: 502.2 (M+H)⁺.

EXAMPLE 6 6-(3,4-DIFLUOROANILINO)-N-[3-(4-PIPERIDINYL) PHENYL]HEXANAMIDE

Into a solution of tert-butyl4-(3-{[6-(3,4-difluoroanilino)hexanoyl]amino}phenyl)-1-piperidinecarboxylate (11.2 mg, 0.0224 mmol) in dichloromethane (0.500 mL) at 0°C. was slowly added trifluoroacetic acid (25.5 mg, 2.24 mmol). Thereaction mixture was stirred at room temperature for 10 min andconcentrated in vacuo. The residue was dissolved in i-PrOH/CHCl₃ (1:3,10 mL) and basified to pH 11 with 10% KOH, washed with H₂O, followed bybrine. The organic layer was dried over MgSO₄ and concentrated in vacuoto give the desired product (8.98 mg, 99%): ¹H NMR (400. MHz, CDCl₃) δ7.39-7.08 (m, 5H), 7.06-6.94 (m, 2H), 6.91-6.81 (m, 1H), 6.77-6.67 (m,1H), 3.54-3.42 (m, 2H), 3.25-3.04 (m, 3H), 2.91-2.80 (m, 1H), 2.45-2.32(m, 2H), 2.11-1.99 (m, 2H), 1.98-1.83 (m, 2H), 1.80-1.62 (m, 4H),1.55-1.40 (m, 2H), 1.34-1.23 (m, 1H); ESMS m/e: 402.2 (M+H)⁺.

The following compounds were prepared according to the Scheme I.

EXAMPLE 1 5-(2-METHOXYPHENYL)-N-[3-(4-PIPERIDINYL)PHENYL]PENTANAMIDE

tert-Butyl4-(3-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylatewas subjected to Scheme I to afford the product. ¹H NMR (400 MHz, CDCl₃)δ 7.52-6.68 (m, 8H), 3.74 (s, 3H), 3.61-3.35 (m, 2H), 3.14-2.90 (m, 2H),2.88-2.56 (m, 3H), 2.52-2.27 (m, 2H), 2.10-1.51 (m, 8H); ESIMS m/e:367.2 [M+H]⁺.

EXAMPLE 2 5-PHENYL-N-[3-(4-PIPERIDINYL)PHENYL]PENTANAMIDE

tert-Butyl 4-{3-[(5-phenylpentanoyl)amino]phenyl}-1-piperidinecarboxylate was subjected to Scheme I to afford the product. ¹H NMR (400MHz, CDCl₃) δ 7.51-6.83 (m, 9H), 3.66-3.40 (m, 2H), 3.08-2.80 (m, 2H),2.78-2.45 (m, 3H), 2.43-2.28 (m, 2H), 2.08-1.60 (m, 8H); ESIMS m/e:337.2 [M+H]⁺.

EXAMPLE 3 6-OXO-6-PHENYL-N-[3-(4-PIPERIDINYL)PHENYL]HEXANAMIDE

tert-Butyl4-{3-[(6-oxo-6-phenylhexanoyl)amino]phenyl}-1-piperidinecarboxylate wassubjected to Scheme I to afford the product. ¹H NMR (400 MHz, CD₃OD) δ7.98-7.83 (m, 2H), 7.60-7.31 (m, 4H), 7.28-7.12 (m, 2H), 6.97-6.87 (m,1H), 3.48-3.31 (m, 2H), 3.10-2.68 (m, 5H), 2.40-2.26 (m, 2H), 2.05-1.63(m, 8H); ESIMS m/e: 365.2 [M+H]⁺.

EXAMPLE 4 2-PHENOXY-N-[3-(4-PIPERIDINYL) PHENYL]NICOTINAMIDE

A mixture of tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate(0.15 mmol), 2-phenoxynicotinoyl chloride (0.23 mmol) and triethylamine(0.30 mmol) in 3 mL of solvent (CH₂Cl₂:THF, 1:3) was stirred at roomtemperature for 12 hours. The reaction mixture was purified bypreparative TLC (silica, EtOAc:hexane 1:1) to afford the desiredproduct, tert-butyl4-(3-{[(2-phenoxy-3-pyridinyl)carbonyl]amino}phenyl)-1-piperidinecarboxylate.Trifluoroacetic acid (1.0 mL) was added to the purified productdissolved in 1.0 mL of CH₂Cl₂ and the solution was stirred at roomtemperature for 1 minute. The reaction mixture was concentrated in vacuoto afford the TFA salt of the desired product. ¹H NMR (400 MHz, CDCl₃) δ9.85 (s, 1H), 8.76-8.64 (br, 1H), 8.30-8.14 (br, 1H), 7.67 (s, 1H), 7.49(t, 2H, J=7.8 Hz), 7.42-7.29 (m, 3H), 7.24 (t, 3H, J=5.2 Hz), 7.03 (d,1H, J=7.2 Hz), 3.59 (bd, 2H, J=11.5), 3.16-3.02 (m, 2H), 2.9-2.79 (m,1H), 2.14-2.01 (m, 4H); ESIMS m/e: 374.1 [M+H]⁺.

EXAMPLE 5 5-(4-METHOXYPHENYL)-N-[3-(4-PIPERIDINYL)PHENYL]PENTANAMIDE

Prepared according to the procedure described in scheme 1

METHYL (2Z)-2-ACETYL-3-(4-FLUOROPHENYL)-2-PROPENOATE

A mixture of 4-fluorobenzaldehyde (25.5 g, 0.220 mol), methyl3-oxobutanoate (21.80 g, 0.220 mol), and piperidine (1.0 mL) inanhydrous benzene (250 mL) was stirred for 10 minutes at roomtemperature and subsequently refluxed overnight in a Dean-Starkapparatus. The reaction mixture was then cooled to room temperature andthe solvent was removed in vacuo to afford methyl(2Z)-2-acetyl-3-(4-fluorophenyl)-2-propenoate as a black solid (48.6 g,99%), which was used for next step without purification.

METHYL6-(4-FLUOROPHENYL)-2-METHOXY-4-METHYL-1,6-DIHYDRO-5-PYRIMIDINECARBOXYLATE

A mixture of methyl (2Z)-2-acetyl-3-(4-fluorophenyl)-2-propenoate (0.220mole, 48.8 g), O-methyl isourea hydrogensulfate (53.40 g, 0.310 mol, 1.5eq.), NaHCO₃ (61.74 g, 0.74 mole, 3.5° equiv.) and ethanol (1.2 L) wasrefluxed for 24 h, cooled to room temperature, and filtered. The solidwas washed with ethanol (200 mL) and the combined filtrate wasconcentrated in vacuo. The residue was purified by chromatography(silica gel, hexanes/EtOAc/Et₃N 50:50:0.1) to yield a mixture oftautomers (4:1, 33.0 g, 53.9%). ¹H NMR (CDCl₃) δ 7.32-7.24 (m, 2H),7.04-6.95 (m, 2H), 5.81 (s, 1H), 5.38 (d, 1H, J=2.9 Hz), 4.00 (s, 3H),3.63 (s, 3H), 2.34 (s, 3H).

5-METHYL 1-(4-NITROPHENYL)6-(4-FLUOROPHENYL)-2-METHOXY-4-METHYL-1,5(6H)-PYRIMIDINEDICARBOXYLATE

To a solution of methyl6-(4-fluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate(1.76 g, 6.34 mmol) and 4-dimethylaminopyridine (12.7 mmol, 1.55 g) inanhydrous CH₂Cl₂ (20.0 mL) was added solution of 4-nitrophenylchloroformate (4.47 g, 22.2 mmol) in CH₂Cl₂ (20.0 mL) at 23° C. Thereaction mixture was stirred for 2 hours at room temperature. Thereaction mixture was diluted with CH₂Cl₂ (50 mL), washed with water,brine, dried over sodium sulfate and concentrated in vacuo. The residuewas purified by flash column chromatography (hexanesiethyl acetate 4:1).The product was obtained as yellow syrup, which upon trituration withhexanes became a white powder (2.40 g, 84.3%). The crude product wasused in next step without further purification.

METHYL1-{[(4-TERT-BUTOXY-4-OXOBUTYL)AMINO]CARBONYL}-6-(4-FLUOROPHENYL)-2-METHOXY-4-METHYL-1,6-DIHYDRO-5-PYRIMIDINECARBOXYLATE

To a solution of 5-methyl1-(4-nitrophenyl)6-(4-fluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate(88.7 mg, 0.200 mmol) and K₂CO₃ (41.5 mg, 0.300 mmol) in CH₃OH/CH₂Cl₂(0.1/2.0 mL) was added tert-butyl 4-aminobutanoate (31.8 mg, 0.200mmol). After stirring at rt for 1 h, the mixture was washed withsaturated Na₂CO₃ and brine. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (5%-10% 2 M NH₃/MeOH in 50% EtOAc/Hexanes) to afford theproduct (92.2 g, 99%). mp 135-138° C.; ¹H NMR (CD₃OD) δ 7.29-7.23 (m,2H), 6.97-6.88 (m, 2H), 6.65 (s, 1H), 3.98 (s, 3H), 3.66 (s, 3H),3.38-3.30 (m, 2H), 2.43 (s, 3H), 2.28 (t, 2H, J=7.2 Hz), 1.89-1.78 (m,2H), 1.43 (s, 9H); ESMS m/e: 464.1 (M+H)⁺.

4-{[(6-(4-FLUOROPHENYL)-5-(METHOXYCARBONYL)-4-METHYL-2-OXO-3,6-DIHYDRO-1(2H)-PYRIMIDINYL)CARBONYL]AMINO}BUTANOICACID

Into a solution of methyl1-{[(4-tert-butoxy-4-oxobutyl)amino]carbonyl}-6-(4-fluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate(77.3 mg, 0.166 mmol) in dichloromethane (2.00 mL) at 0° C. was slowlyadded trifluoroacetic acid (189 mg, 1.66 mmol). The reaction mixture wasstirred at room temperature for 10 min and concentrated in vacuo. Theresidue was dissolved in iso-PrOH/CHCl₃ (1:3, 10 mL) and basified to pH11 with 10% KOH solution, washed with H₂O, followed by brine. Theorganic layer was dried over MgSO₄ and concentrated in vacuo to affordthe desired product (58.1 mg, 88.9%). ESMS m/e: 394.1 (M+H)⁺.

METHYL3-{[(4-{3-[1-(TERT-BUTOXYCARBONYL)-4-PIPERIDINYL]ANILINO}-4-OXOBUTYL)AMINO]CARBONYL}-4-(4-FLUOROPHENYL)-6-METHYL-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE

A 10-mL RB-flask was charged with4-{[(6-(4-fluorophenyl)-5-(methoxycarbonyl)-4-methyl-2-oxo-3,6-dihydro-1(2H)-pyrimidinyl)carbonyl]amino}butanoicacid (77.0 mg, 0.189 mmol),tert-butyl-4-[3-(amino)phenyl]-1-piperidinecarboxylate (52.2 mg, 0.189mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride(0.567 mmol, 87.8 mg), 4-dimethylaminopyridine (11.5 mg, 0.0945 mmol) inDMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture wasstirred for 12 h and water (10.0 mL) was added to the reaction mixture.The organic layer was separated and the aqueous layer was extracted withCHCl₃ (3×10 mL). The combined organic extracts were washed with brine,dried over MgSO₄₁ filtered and concentrated in vacuo. The residue waschromatographed (silica, hexanes:EtOAc 9:1) to afford the desiredproduct (40.9 mg, 33.2%): ¹H NMR (400 MHz, CDCl₃) δ 8.03 (m, 3H), 7.57(s, 1H), 7.36-7.28 (m, 3H), 7.27-7.22 (m, 1H), 6.97-6.89 (m, 3H), 6.72(s, 1H), 3.72 (s, 3H), 3.47-3.37 (m, 2H), 2.42 (s, 3H), 2.37-2.29 (m,2H), 1.98-1.91 (m, 2H), 1.86-1.75 (m, 2H), 1.72-1.54 (m, 7H), 1.48 (s,9H); ESMS m/e: 652.2 (M+H)⁺.

EXAMPLE 7 METHYL4-(4-FLUOROPHENYL)-6-METHYL-2-OXO-3-[({4-OXO-4-[3-(4-PIPERIDINYL)ANILINO]BUTYL}AMINO)CARBONYL]-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE

Into a solution of methyl3-{[(4-{3-[1-(tert-butoxycarbonyl)-4-piperidinyl]anilino}-4-oxobutyl)amino]carbonyl}-4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate(40.9 mg, 0.0628 mmol) in dichloromethane (2.00 mL) at 0° C. was slowlyadded trifluoroacetic acid (71.6 mg, 0.628 mmol). The reaction mixturewas stirred at room temperature for 10 min and concentrated in vacuo.The residue was dissolved in iso-PrOH/CHCl₃ (1:3, 10 mL) and basified topH 11 with 10% KOH solution, washed with H₂O, followed by brine. Theorganic layer was dried over MgSO₄ and concentrated in vacuo to affordthe desired product (34.6 mg, 99%): ¹H NMR (400 MHz, CDCl₃) δ 8.00 (m,3H), 7.67 (s, 1H), 7.35-7.27 (m, 4H), 7.04-6.98 (m, 3H), 6.65 (s, 1H),3.72 (s, 3H), 3.5-3.48 (m, 2H), 3.20-3.11 (m, 3H), 2.42 (t, 2H, J=7.5Hz), 2.36 (s, 3H), 2.13-2.06 (m, 2H), 1.97-1.88 (m, 4H); ESMS m/e: 552.3(M+H)⁺.

TERT-BUTYL-4-{3-[(4-{[(5-METHOXYLCARBONYL-6-(3,4-DIFLUOROPHENYL)-4-METHYL-2-OXO-3,6-DIHYDRO-1(2H)-PYRIMIDINYL)CARBONYL]AMINO}BUTANOYL)AMINO]PHENYL}-1-PIPERIDINECARBOXYLATE

A 50-mL RB-flask was charged with4-{[(5-acetyl-6-(3,4-difluorophenyl)-4-methyl-2-oxo-3,6-dihydro-1(2H)-pyrimidinyl)carbonyl]amino}butanoicacid (313 mg, 0.854 mmol),tert-butyl-4-[3-(amino)phenyl]-1-piperidinecarboxylate (235 mg, 0.857mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimide hydrochloride(7.71 mmol, 265 mg), 4-dimethylaminopyridine (10.4 mg, 0.0854 mmol) inDMF:DCM (0.8:8.0 mL) at room temperature. The reaction mixture wasstirred for 12 h and water (20.0 mL) was added to the reaction mixture.The organic layer was separated and the aqueous layer was extracted withCHCl₃ (3×10 mL). The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. The residue waschromatographed (silica, hexanes:EtOAc 9:1) to afford the desiredproduct (378 mg, 67.8%): ¹H NMR (400 MHz, CDCl₃) δ 8.03 (m, 2H), 7.57(s, 1H), 7.36-7.28 (m, 3H), 7.27-7.22 (m, 1H), 6.97-6.89 (m, 3H), 6.72(s, 1H), 3.72 (s, 3H), 3.47-3.37 (m, 2H), 2.42 (s, 3H), 2.37-2.29 (m,2H), 1.98-1.91 (m, 2H), 1.86-1.75 (m, 2H), 1.72-1.54 (m, 7H), 1.48 (s,9H); ESMS m/e: 554.3 (M−100).

EXAMPLE 85-METHOXYLCARBONYL-6-(3,4-DIFLUOROPHENYL)-4-METHYL-2-OXO-N-{4-OXO-4-[3-(4-PIPERIDINYL)ANILINO]BUTYL}-3,6-DIHYDRO-1(2H)-PYRIMIDINECARBOXAMIDE

Into a solution of tert-butyl4-{3-[(4-{[(5-Methoxylcarbonyl-6-(3,4-difluorophenyl)-4-methyl-2-oxo-3,6-dihydro-1(2H)-pyrimidinyl)carbonyl]amino}butanoyl)amino]phenyl}-1-piperidinecarboxylate(378 mg, 0.579 mmol) in dichloromethane (5.00 mL) at 0° C. was slowlyadded trifluoroacetic acid (659 mg, 5.79 mmol). The reaction mixture wasstirred at room temperature for 10 min and concentrated in vacuo. Theresidue was dissolved in iso-PrOH/CHCl₃ (1:3, 10 mL) and basified to pH11 with 10% KOH solution, washed with H₂O, followed by brine. Theorganic layer was dried over MgSO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography (dichloromethane:methanol5:1) to afford the desired product (93.8 mg, 29.3%): ¹H NMR (400 MHz,CDCl₃) δ 7.46-7.43 (m, 3H), 7.35-7.29 (m, 2H), 7.12-7.06 (m, 3H),6.63-6.60 (m, 1H), 6.56-6.52 (m, 2H), 3.26 (s, 3H), 3.22 (s, 3H), 2.72(dt, 6H, J=2.3, 12.3 Hz), 2.66 (tt, 2H, J=3.6, 11.9 Hz), 2.55 (tt, 1H,J=3.8, 11.9 Hz), 1.88-1.82 (m, 1H), 1.75-1.63 (m, 6H); ESMS m/e: 554.3(M+H)⁺.General Procedure for Piperidine Synthesis (Scheme 2)

TERT-BUTYL4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE

To a 50-mL RB-flask, charged with bis(pinacolato)diboron (422 mg, 1.66mmol), KOAc (444 mg, 4.53 mmol), PdCl₂dppf (37.0 mg, 3.00 mol %) anddppf (25.0 mg; 3.00 mol %) was added a solution of tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate(500 mg, 1.51 mmol) in 1,4-dioxane (10.0 mL) at room temperature underargon. The mixture was heated at 80° C. overnight. After cooling to roomtemperature, the mixture was filtered through Celite and the Celite waswashed with EtOAc (3×20 mL) The combined filtrates were washed with H₂Oand brine, dried over MgSO₄, filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography (EtOAc:hexanes 1:9)to afford tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate(355 mg, 76%): ¹H NMR (400 MHz, CDCl₃) δ 6.60-6.34 (br, 1H), 4.06-3.86(br, 2H), 3.55-3.34 (br, 2H), 2.35-2.09 (br, 2H), 1.46 (s, 9H), 1.26 (s,12H); ESMS m/e: 310.4 (M+H)⁺.

5-BROMO-2,4-DIFLUORONITROBENZENE

To a suspension of 1-bromo-2,4-difluorobenzene (53.0 mmol, 6.00 mL) inconcentrated H₂SO₄ (38.5 mL) at 0° C. was added dropwise concentratedHNO₃ (34.0 mL) maintaining internal temperature below 20° C. Theresulting mixture was stirred for 10 min at 0° C., then poured intoice/water with vigorous stirring. The mixture was extracted with Et₂O(3×100 mL). The combined organic extracts were washed with aqueousNaHCO₃ solution (3×100 mL) and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (EtOAc:hexanes 1:9) to afford5-bromo-2,4-difluoronitrobenzene as a yellow oil (12.2 g, 97%). ¹H NMR(400 MHz, CDCl₃) δ 8.45 (t, 1H, J=7.5 Hz), 7.16 (dd, 1H, J=11.0, 8.6Hz); ESMS m/e: 240, 238, 223, 221, 112

5-BROMO-2,4-DIFLUOROANILINE

A 250-mL RB-flask, charged with 5-bromo-2,4-difluoronitrobenzene (5.04g, 21.3 mmol), saturated NH₄Cl (25.0 mL), iron powder (5.00 g, 89.5mmol), ethanol (100 mL), THF (50.0 mL) and water (25.0 mL) was refluxedat 95° C. for 1.5 hours. After cooling to room temperature, saturatedNaHCO₃ (100 mL) was added and the mixture was filtered through Celiteand the Celite was washed with EtOAc (3×50 mL). The combined filtrateswere washed with H₂O and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (EtOAc:hexanes 1:9) to afford5-bromor-2,4-difluoroaniline (2.61 g, 59.1%). ¹H NMR (400 MHz, CDCl₃) δ6.97 (dd, 1H, J=7.2, 6.7 Hz), 6.85 (t, 1H, J=8.2 Hz), 3.63 (br, 2H).

BENZYL 5-BROMO-2,4-DIFLUOROPHENYLCARBAMATE

Into a 250-mL RB-flask was added 5-bromor-2,4-difluoroaniline (5.00 g,24.2 mmol), chlorobenzylformate (4.10 mL, 29.0 mmol), NaHCO₃ (6.10 g,72.6 mmol) and acetonitrile (100 mL). The reaction mixture was stirredat 25° C. for 12 hours, then filtered through a coarse sintered glass,fritted funnel, washed with EtOAc (3×20 mL) and concentrated in vacuo.The filtrate was washed with H₂O and brine, dried over MgSO₄, filteredand concentrated in vacuo. The crude product was purified by flashchromatography (EtOAc:hexanes 1:9) to afford benzyl5-bromor-2,4-difluorophenylcarbamate (5.05 g, 61.0%): ¹H NMR (400 MHz,CDCl₃) δ 8.38 (s, 1H), 7.49-7.31 (m, 5H), 6.94-6.89 (m, 1H), 6.81-6.77(m, 1H), 5.22 (s, 2H); ESMS m/e: 340.1 (M−H⁺).

TERT-BUTYL4-(5-{[(BENZYLOXY)CARBONYL]AMINO}-2,4-DIFLUOROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE

To a 250-mL RB-flask containing tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate(4.58 g, 14.8 mmol), K₂CO₃ (6.14 g, 44.4 mmol) and PdCl₂dppf (1.48 mmol,1.21 g) was added a solution of benzyl5-bromo-2,4-difluorophenylcarbamate (5.05, 14.8 mmol) in DMF (150 mL) atroom temperature under argon. The mixture was heated to 80° C. underargon overnight. After cooling to room temperature, the mixture wasfiltered through Celite and the Celite was washed with EtOAc (3×100 mL).The filtrates were washed with H₂O (3×200 mL), brine (100 mL), driedover MgSO₄₁ filtered and concentrated in vacuo. The crude material waspurified flash chromatography (EtOAc/hexanes 1:9) to afford tert-butyl4-(5-{[(benzyloxy)carbonyl]amino}-2,4-difluorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(1.60 g, 24.5%): ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.45-7.35 (m,5H), 6.85-6.70 (m, 1H), 5.95-5.85 (m, 1H), 5.20 (s, 2H), 4.05 (m, 2H),3.6-3.5 (m, 2H), 2.5-2.4 (m, 2H), 1.50 (s, 9H); ESMS m/e: 443.3 (M−H⁺).

TERT-BUTYL 4-(5-AMINO-2,4-DIFLUOROPHENYL)-1-PIPERIDINECARBOXYLATE

A mixture of tert-butyl4-(5-{[(benzyloxy)carbonyl]amino}-2,4-difluorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate(1.60 g, 3.60 mmol) and 5% Pd/C (320 mg, 0.100 mmol) in ethyl acetate(25.0 mL) and methanol (25.0 mL) was hydrogenated at room temperaturefor 72 hours using hydrogen bomb (200 psi). The reaction mixture wasfiltered through Celite and washed with EtOAc/MeOH (1:1, 3×50 mL). Thefiltrate was concentrated in vacuo to afford tert-butyl4-(5-amino-2,4-difluorophenyl)-1-piperidinecarboxylate (1.39 g, 100%).¹H NMR (400 MHz, CDCl₃) δ 6.73 (t, 1H, J=10.6 Hz), 6.60-6.54 (dd, 1H,J=7.6, 6.57 Hz), 4.20 (br, 2H), 3.55 (s, 2H), 2.96-2.72 (m, 3H),1.79-1.71 (m, 2H), 1.58-1.52 (m, 2H), 1.47 (s, 9H); ESMS m/e: 257.3(M-56).

ETHYL (4E)-5-(2-METHOXYPHENYL)-4-PENTENOATE

To a 200-mL RB-flask was added 2-iodoanisole (5.00 g, 21.4 mmol), ethyl4-pentenoate (3.30 g, 25.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.740 g, 0.600 mmol), triethylamine (6.00 mL,42.7 mmol) and a mixture of CH₃CN (45.0 mL) and THF (15.0 mL). Thereaction mixture was refluxed for overnight and then cooled to roomtemperature. After solvents were removed in vacuo, the resulted darkbrown residue was dissolved in 5% HCl (aq) and extracted with CH₂Cl₂three times. The combined extracts were washed by saturated NaHCO₃solution, dried over MgSO₄, concentrated in vacuo. The dark brown oilwas purified by chromatography (silica gel, EtOAc/Hexanes 1:10) toafford the product as light yellow oil (3.40 g, 68%).

ETHYL 5-(2-METHOXYPHENYL)PENTANOATE

To a solution of ethyl (4E)-5-(2-methoxyphenyl)-4-pentenoate (3.40 g,14.5 mmol) in a mixture of EtOAc and MeOH (40.0/10.0 mL), Pd/C(palladium on carbon 10%, 0.700 g) was added in small portions to avoidfire. The reaction mixture was then stirred for overnight at roomtemperature under 300 psi of hydrogen. After the pressure was released,the mixture was filtered through Celite and the Celite was washed withEtOAc (3×50 mL). The filtrate was concentrated in vacuo to afford crudeproduct as a light yellow oil (3.40 g 100%), which was used withoutfurther purification.

5-(2-METHOXYPRENYL)PENTANOIC ACID

Into a 250-mL RB-flask was charged with ethyl5-(2-methoxyphenyl)pentanoate (3.40 g, 14.5 mmol), NaOH (1.74 g, 42.8mmol), THF (25.0 mL) and water (25.0 mL). The reaction mixture wasrefluxed for 2 hours and cooled to room temperature. The reactionmixture was concentrated in vacuo and the resulted aqueous solution wasacidified with 6 M HCl to pH <5. The acidic mixture was extracted withchloroform/isopropyl alcohol (3:1, 3×50 mL) and the combined organicphases were washed with brine, dried over Na₂SO₄ and concentrated invacuo to afford the product as a white solid (2.68 g, 90%), which wasused without further purification. ¹H NMR (400 MHz, MeOD) δ 7.23-7.03(m, 2H), 6.95-6.76 (m, 2H), 3.81 (s, 3H), 2.63 (t, 2H, J=7.2 Hz), 2.38(t, 2H, J=7.2 Hz), 1.77-1.53 (m, 4H)

TERT-BUTYL4-(2,4-DIFLUORO-5-{[5-(2-METHOXYPHENYL)PENTANOYL]AMINO}PHENYL)-1-PIPERIDINECARBOXYLATE

A 15-mL RB-flask was charged with 5-(2-methoxyphenyl)pentanoic acid(69.0 mg, 0.810 mmol), tert-butyl4-(5-amino-2,4-difluorophenyl)-1-piperidinecarboxylate (229 mg, 0.740mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimide hydrochloride(2.22 mmol, 426 mg), 4-dimethylaminopyridine (9 mg, 0.07 mmol) inDMF:DCM (0.2:5.0 mL) at room temperature. The reaction mixture wasstirred for 12 h and water (10.0 mL) was added to the reaction mixture.

The organic layer was separated and the aqueous layer was extracted withCHCl₃ (3×10 mL). The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo to affordtert-butyl4-(2,4-difluoro-5-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylate(310 mg, 83.2%): ¹H NMR (400 MHz, CDCl₃) δ 8.36-8.13 (m, 1H), 7.39 (s,1H), 7.26-7.06 (m, 1H), 7.06-6.92 (m, 1H), 6.92-6.75 (m, 3H), 4.41-4.02(m, 2H), 3.80 (s, 3H), 2.90-2.70 (m, 2H), 2.70-2.63 (m, 2H), 2.63-2.51(m, 1H), 2.49-2.32 (m, 2H), 1.87-1.72 (m, 4H), 1.72-1.63 (m, 2H),1.63-1.52 (m, 2H), 1.48 (s, 9H).

EXAMPLE 11N-[2,4-DIFLUORO-5-(4-PIPERIDINYL)PHENYL]-5-(2-METHOXYPHENYL)PENTANAMIDE

Into a solution of tert-butyl4(2,4-difluoro-5-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylate(310 mg, 0.620 mmol) in dichloromethane (5.00 mL) at 0° C. was slowlyadded trifluoroacetic acid (707 mg, 6.20 mmol). The reaction mixture wasstirred at room temperature for 10 min and concentrated in vacuo. Theresidue was dissolved in i-PrOH/CHCl₃ (1:3, 10 mL) and basified to pH 11with 10% KOH solution, washed with H₂O, followed by brine. The organiclayer was separated, dried over MgSO₄ and concentrated in vacuo toafford the desired product (108 mg, 43.3%). ¹H NMR (400 MHz, CDCl₃) δ7.59 (t, 1H, J=8.2 Hz), 7.10-6.96 (m, 2H), 6.90-6.68 (m, 3H), 3.67 (s,3H), 3.09 (d, 2H, J=12.4 Hz), 2.89 (tt, 1H, J=11.8 Hz), 2.69 (dt, 2H,J=2.6, 12.4 Hz), 2.54 (t, 2H, J=7.2 Hz), 2.33 (t, 2H, J=7.2 Hz),1.76-1.48 (m, 8H); ESMS m/e: 403.3 (M+H)⁺.General Procedure for Piperidine Synthesis (Scheme 3)

TERT-BUTYL4-(4-FLUORO-3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE

To a 150-mL RB-flask containing tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate(5.58 g, 16.5 mmol), K₂CO₃ (5.60 g, 40.5 mmol) and PdCl₂dppf (1.48 mmol,1.21 g) was added a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.30 g,15.0 mmol) in DMF (50.0 mL) at room temperature under argon. The mixturewas heated to 80° C. under argon for 12 hours. After cooling to roomtemperature, the mixture was filtered through Celite and the Celite waswashed with EtOAc (3×100 mL). The filtrates were washed with H₂O (3×200mL), brine (100 mL), dried over MgSO₄, filtered and concentrated invacuo. The crude material was purified by flash chromatography(EtOAc/hexanes 1:9) to afford tert-butyl4-(4-fluoro-3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.13g, 65.1%): ¹H NMR (400 MHz, CDCl₃) δ 8.06-7.89 (m, 1H), 7.66-7.49 (m,1H), 7.30-7.10 (m, 1H), 6.19-5.95 (br, 1H), 4.10-3.95 (m, 2H), 3.58 (t,2H, J=5.6 Hz), 2.49-2.34 (m, 2H), 1.42 (s, 9H).

TERT-BUTYL-4-(3-AMINO-4-FLUOROPHENYL)-1-PIPERIDINECARBOXYLATE

A mixture of tert-butyl4-(4-fluoro-3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (2.35g, 8.85 mmol) and 10% Pd/C (400 mg) in ethyl acetate (40.0 mL) andmethanol (10.0 mL) was hydrogenated at room temperature for 72 hoursusing hydrogen bomb (200 psi). The reaction mixture was filtered throughCelite and the Celite was washed with EtOAc/MeOH (1:1, 3×50 mL). Thefiltrate was concentrated in vacuo to affordtert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (2.10 g,98.0%): ¹H NMR (400 MHz, CDCl₃) δ 6.96-6.76 (m, 1H), 6.67-6.54 (m, 1H),6.54-6.40 (m, 1H), 4.38-4.09 (br, 2H), 4.09-3.58 (br, 2H), 2.87-2.62 (m,2H), 2.60-2.39 (m, 1H), 1.85-1.65 (m, 2H), 1.64-1.40 (m, 2H), 1.48 (s,9H).

TERT-BUTYL4-(4-FLUORO-3-{[5-(2-METHOXYPHENYL)PENTANOYL]AMINO}PHENYL)-1-PIPERIDINECARBOXYLATE

A 25-mL RB-flask was charged with 5-(2-methoxyphenyl)pentanoic acid(53.0 mg, 0.250 mmol),tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (59.0 mg,0.200 mmol), 1-[3-(Dimethylamino)propyl)-3-ethylcarbodimidehydrochloride (0.400 mmol, 62.0 mg), 4-dimethylaminopyridine (10 mg) inDMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture wasstirred for 12 h and water (10.0 mL) was added to the reaction mixture.The organic layer was separated and the aqueous layer was extracted withCHCl₃ (3×10 mL) The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. The crude residuewas purified by chromatography (silica gel, hexanes:EtOAc 6:1) to affordtert-butyl4-(4-fluoro-3-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1-piperidinecarboxylate(48.4 mg, 50.0%): ¹H NMR (400 MHz, CDCl₃) δ 8.36-8.13 (m, 1H), 7.39 (s,1H), 7.26-7.06 (m, 2H), 7.06-6.92 (m, 1H), 6.92-6.75 (m, 3H), 4.41-4.02(m, 2H), 3.80 (s, 3H), 2.90-2.70 (m, 2H), 2.70-2.63 (m, 2H), 2.63-2.51(m, 1H), 2.49-2.32 (m, 2H), 1.87-1.72 (m, 4H), 1.72-1.63 (m, 2H),1.63-1.52 (m, 2H), 1.48 (s, 9H).

EXAMPLE 10N-[2-FLUORO-5-(4-PIPERIDINYL)PHENYL]-5-(2-METHOXYPHENYL)PENTANAMIDE

Into a solution of tert-butyl4-(4-fluoro-3-{[5-(2-methoxyphenyl)pentanoyl]amino}phenyl)-1piperidinecarboxylate(48.4 mg, 0.100 mmol) in CH₂Cl₂ (2.0 mL) was added trifluoroacetic acid(114 mg, 1.0 mmol) at room temperature. The reaction mixture was stirredfor 30 min and concentrated in vacuo. The residue was dissolved inCHCl₃/i-PrOH (3:1, 10 mL) and was basified to pH 11 with 5% KOHsolution. The organic layer was separated and the aqueous layer wasextracted with CHCl₃/i-PrOH (3:1, 3×10 mL). The combined organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to afford affordN-[2-fluoro-5-(4-piperidinyl)phenyl]-5-(2-methoxyphenyl)pentanamide(38.0 mg, 95%): ¹H NMR (400 MHz, CD₃OD) δ 8.30-8.12 (m, 1H), 7.64-7.41(m, 1H), 7.24-7.07 (m, 2H), 7.06-6.92 (m, 1H), 6.92-6.74 (m, 3H), 3.80(s, 3H), 3.25-3.06 (m, 2H), 2.80-2.49 (m, 5H), 2.48-2.24 (m, 3H),1.89-1.71 (m, 4H), 1.71-1.46 (m, 4H); ESMS m/e: 385.2 (M+H)⁺.

3-[4-(3,4-DIFLUOROPHENOXY)PHENYL]PROPANOIC ACID

In a 50-mL RB-flask was added 3-(4-hydroxyphenyl)propionic acid (1.66 g,10.0 mmol), 3,4-difluoroiodobenzene (2.40 g, 10.0 mmol), copper(I)bromide (0.100 g), potassium carbonate (2.76 g, 20.0 mmol), andn-methyl-2-pyrrolidone (20 mL) as solvent. The mixture was stirred for 5min at room temperature and then heated to 140° C. (oil bath). Afterbeing stirred for 12 hours at 140° C., the reaction mixture was cooledto room temperature and diluted with EtOAC (100 mL). The diluted mixturewas washed with citric acid (aq, 30 mL), water (3×50 mL, brine and driedover MgSO₄. The removal of solvent in vacuo afforded crude which waspurified by chromatography (0.901 g, 32%): ¹H NMR (400 MHz, CDCl₃) δ11.44-11.06 (br, 1H), 7.24-7.14 (m, 2H), 7.14-7.00 (m, 1H), 7.00-6.86(m, 2H), 6.86-6.75 (m, 1H), 6.75-6.61 (m, 1H), 2.94 (t, 2H, J=7.6 Hz),2.68 (t, 2H, J=7.6 Hz); ESMS m/e: 277.2 (M−H⁺).

TERT-BUTYL-4-[3-({3-[4-(3,4-DIFLUOROPHENOXY)PHENYLIPROPANOYL}AMINO)-4-FLUOROPHENYL]-1-PIPERIDINECARBOXYLATE

A 25-mL RB-flask was charged with3-[4-(3,4-difluorophenoxy)phenyl]propanoic acid (180 mg, 0.650 mmol),tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidine carboxylate (180 mg,0.610 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimidehydrochloride (1.22 mmol, 190 mg), 4-dimethylaminopyridine (20 mg) inDMF:DCM (0.4:4.0 mL) at room temperature. The reaction mixture wasstirred for 12 h and water (10.0 mL) was added to the reaction mixture.The organic layer was separated and the aqueous layer was extracted withCHCl₃ (3×10 mL) The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. The crude residuewas purified by chromatography (silica gel, hexanes:EtOAc 6:1) to affordtert-butyl4-[3-({3-(4-(3,4-difluorophenoxy)phenyl]propanoyl}amino)-4-fluorophenyl]-1-piperidinecarboxylate(85.0 mg, 25.0%): ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.15 (m, 1H), 7.47-6.45(m, 10H), 4.41-4.07 (br, 2H), 3.17-2.96 (m, 2H), 2.90-2.67 (m, 4H),2.67-2.56 (m, 1H), 1.91-1.69 (m, 2H), 1.68-1.48 (m, 2H), 1.47 (s, 9H);ESMS m/e 553.3 (M−H⁺).

EXAMPLE 123-[4-(3,4-DIFLUOROPHENOXY)PHENYL]-N-[2-FLUORO-5-(4-PIPERIDINYL)PHENYL]PROPANAMIDE

Into a solution oftert-butyl-4-[3-({3-[4-(3,4-difluorophenoxy)phenyl]propanoyl}amino)-4-fluorophenyl]-1-piperidinecarboxylate(85.0 mg, 0.150 mmol) in CH₂Cl₂ (2.0 mL) was added trifluoroacetic acid(170 mg, 1.50 mmol) at room temperature. The reaction mixture wasstirred for 10 min and concentrated in vacuo. The residue was dissolvedin CHCl₃/i-PrOH (3:1, 10 mL) and was basified to pH 11 with 5% KOHsolution. The organic layer was extracted and the aqueous layer wasextracted with CHCl₃/i-PrOH (3:1, 3×10 mL). The combined organicextracts were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to afford3-[4-(3,4-difluorophenoxy)phenyl]-N-[2-fluoro-5-(4-piperidinyl)phenyl]propanamide(65.0 mg, 92%): ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.12 (m, 1H), 7.39 (s,1H), 7.33-7.17 (m, 2H), 7.17-7.06 (m, 1H), 7.06-6.97 (m, 1H), 6.97-6.87(m, 3H), 6.86-6.74 (m, 1H), 6.74-6.62 (m, 1H), 6.15-5.63 (br, 1H),3.55-3.31 (m, 2H), 3.15-2.97 (m, 2H), 2.97-2.79 (m, 2H), 2.79-2.59 (m,3H), 2.05-1.79 (m, 4H); ESMS m/e: 455.2 (M+H)⁺.

TERT-BUTYL4-{4-FLUORO-3-[(6-OXO-6-PHENYLHEXANOYL)AMINO]PHENYL}-1-PIPERIDINECARBOXYLATE

A 25-mL RB-flask was charged with 6-oxo-6-phenylhexanoic acid (51.0 mg,0.250 mmol),tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (59.0 mg,0.200 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimidehydrochloride (0.400 mmol, 62.0 mg), 4-dimethylaminopyridine (10 mg) inDMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture wasstirred for 12 h and water (10.0 mL) was added to the reaction mixture.The organic layer was separated and the aqueous layer was extracted withCHCl₃ (3×10 mL). The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. The crude residuewas purified by chromatography (silica gel, hexanes:EtOAc 6:1) to affordtert-butyl4-{4-fluoro-3-[(6-oxo-6-phenylhexanoyl)amino]phenyl}-1-piperidinecarboxylate(49.0 mg, 51.0%): ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.14 (m, 1H), 8.04-7.89(m, 2H), 7.62-7.50 (m, 1H), 7.50-7.37 (m, 3H), 7.09-6.93 (m, 1H),6.93-6.76 (m, 1H), 4.38-4.01 (br, 2H), 3.13-2.95 (m, 2H), 2.89-2.69 (m,2H), 2.65-2.54 (m, 1H), 2.54-2.35 (m, 2H), 1.95-1.74 (m, 6H), 1.69-1.48(m, 2H), 1.47 (s, 9H).

EXAMPLE 9 N-[2-FLUORO-5-(4-PIPERIDINYL) PHENYL]-6-OXO-6-PHENYLHEXANAMIDE

Into a solution of tert-butyl4-{4-fluoro-3-[(6-oxo-6-phenylhexanoyl)amino]phenyl}-1-piperidinecarboxylate (49.0 mg, 0.101 mmol) in CH₂Cl₂ (3.0 mL) was addedtrifluoroacetic acid (114 mg, 1.01 mmol) at room temperature. Thereaction mixture was stirred for 30 min and concentrated in vacuo. Theresidue was dissolved in CHCl₃/i-PrOH (3:1, 10 mL) and was basified topH 11 with 5% KOH solution. The organic layer was separated and theaqueous layer was extracted with CHCl₃/i-PrOH (3:1, 3×10 mL). Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo to affordN-[2-fluoro-5-(4-piperidinyl)phenyl]-6-oxo-6-phenylhexanamide (35.5 mg,86.0%). HCl salt: ¹H NMR (400 MHz, CDCl₃) δ 8.14-8.01 (br, 1H),8.01-7.89 (m, 2H), 7.65-7.52 (m, 1H), 7.52-7.43 (m, 2H), 7.43-7.26 (br,1H), 7.13-7.00 (m, 1H), 7.00-6.88 (br, 1H), 3.68-3.43 (m, 2H), 3.19-2.92(br, 4H), 2.89-2.67 (m, 1H), 2.61-2.36 (br, 2H), 2.26-2.06 (m, 2H),2.06-1.93 (m, 2H), 1.93-1.71 (br, 4H); ESMS m/e: 383.2 (M+H)⁺.

II. Synthetic Methods for General Structures

The examples described in Section I are merely illustrative of themethods used to synthesize MCH1 antagonists. Further derivatives may beobtained utilizing generalized methods based on the synthetic methodsused to synthesize the examples.

It may be necessary to incorporate protection and deprotectionstrategies for substituents such as amino, amido, carboxylic acid, andhydroxyl groups in the generalized synthetic methods to form furtherderivatives.

Methods for protection and deprotection of such groups are well-known inthe art, and may be found, for example in Green, T. W. and Wuts, P. G.M. (1991) Protection Groups in Organic Synthesis, 2^(nd) Edition JohnWiley & Sons, New York.

III. Oral Compositions

As a specific embodiment of an oral composition of a compound of thisinvention, 100 mg of one of the compounds described herein is formulatedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size O hard gel capsule.

IV. Pharmacological Evaluation of Compounds at Cloned Rat MCH1 Receptor

The pharmacological properties of the compounds of the present inventionwere evaluated at the cloned rat MCH1 receptor using protocols describedbelow.

Host Cells

A broad variety of host cells can be used to study heterologouslyexpressed proteins. These cells include but are not restricted toassorted mammalian lines such as: Cos-7, CHO, LM(tk-), HEK293, Peakrapid 293, etc.; insect cell lines such as: Sf9, Sf21, etc.; amphibiancells such as xenopus oocytes; and others.

COS 7 cells are grown on 150 mm plates in DMEM with supplements(Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mMglutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37° C., 5%CO₂. Stock plates of COS-7 cells are trypsinized and split 1:6 every 3-4days.

Human embryonic kidney 293 cells are grown on 150 mm plates in DMEM withsupplements (10% bovine calf serum, 4 mM glutamine, 100 units/mlpenicillin/100 Fg/ml streptomycin) at 37° C., 5% CO₂. Stock plates of293 cells are trypsinized and split 1:6 every 3-4 days.

Human embryonic kidney Peak rapid 293 (Peakr293) cells are grown on 150mm plates in DMEM with supplements (10% fetal bovine serum, 10%L-glutamine, 50 Fg/ml gentamycin) at 37° C., 5% CO₂. Stock plates ofPeak rapid 293 cells are trypsinized and split 1:12 every 3-4 days.

Mouse fibroblast LM(tk-) cells are grown on 150 mm plates in DMEM withsupplements (Dulbecco's Modified Eagle Medium with 10% bovine calfserum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin)at 37° C., 5% CO₂. Stock plates of LM(tk-) cells are trypsinized andsplit 1:10 every 3-4 days.

Chinese hamster ovary (CHO) cells were grown on 150 mm plates in HAM=sF-12 medium with supplements (10% bovine calf serum, 4 mM L-glutamineand 100 units/ml penicillin/100 Fg/ml streptomycin) at 37° C., 5% CO₂.Stock plates of CHO cells are trypsinized and split 1:8 every 3-4 days.

Mouse embryonic fibroblast NIH-3T3 cells are grown on 150 mm plates inDulbecco=s Modified Eagle Medium (DMEM) with supplements (10% bovinecalf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/mlstreptomycin) at 37° C., 5% CO₂. Stock plates of NIH-3T3 cells aretrypsinized and split 1:15 every 3-4 days.

Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue culturedishes in TMN-FH media supplemented with 10% fetal calf serum, at 27°C., no CO₂. High Five insect cells are grown on 150 mm tissue culturedishes in Ex-Cell 400™ medium supplemented with L-Glutamine, also at 27°C., no CO₂.

In some cases, cell lines that grow as adherent monolayers can beconverted to suspension culture to increase cell yield and provide largebatches of uniform assay material for routine receptor screeningprojects.

Transient Expression

DNA encoding proteins to be studied can be transiently expressed in avariety of mammalian, insect, amphibian and other cell lines by severalmethods including but not restricted to; calcium phosphate-mediated,DEAE-dextran mediated, Liposomal-mediated, viral-mediated,electroporation-mediated and microinjection delivery. Each of thesemethods may require optimization of assorted experimental parametersdepending on the DNA, cell line, and the type of assay to besubsequently employed.

A typical protocol for the calcium phosphate method as applied to Peakrapid 293 cells is described as follows:

Adherent cells are harvested approximately twenty-four hours beforetransfection and replated at a density of 3.5×10⁶ cells/dish in a 150 mmtissue culture dish and allowed to incubate over night at 37° C. at 5%CO₂. 250 Fl of a mixture of CaCl₂ and DNA (15 Fg DNA in 250 mM CaCl₂) isadded to a 5 ml plastic tube and 500 Fl of 2×HBS (280 mM NaCl, 10 mMKCl, 1.5 mM Na₂HPO₄, 12 mM dextrose, 50 mM HEPES) is slowly added withgentle mixing. The mixture is allowed to incubate for 20 minutes at roomtemperature to allow a DNA precipitate to form. The DNA precipitatemixture is then added to the culture medium in each plate and incubatedfor 5 hours at 37° C., 5% CO₂. After the incubation, 5 ml of culturemedium (DMEM, 10% FBS, 10% L-glut and 50 μg/ml gentamycin) is added toeach plate. The cells are then incubated for 24 to 48 hours at 37° C.,5% CO₂.

A typical protocol for the DEAE-dextran method as applied to Cos-7 cellsis described as follows; Cells to be used for transfection are split 24hours prior to the transfection to provide flasks which are 70-80%confluent at the time of transfection. Briefly, 8 Fg of receptor DNAplus 8 Fg of any additional DNA needed (e.g. G_(α) protein expressionvector, reporter construct, antibiotic resistance marker, mock vector,etc.) are added to 9 ml of complete DMEM plus DEAE-dextran mixture (10mg/ml in PBS).

Cos-7 cells plated into a T225 flask (sub-confluent) are washed oncewith PBS and the DNA mixture is added to each flask. The cells areallowed to incubate for 30 minutes at 37° C., 5% CO₂. Following theincubation, 36 ml of complete DMEM with 80 FM chloroquine is added toeach flask and allowed to incubate an additional 3 hours. The medium isthen aspirated and 24 ml of complete medium containing 10% DMSO forexactly 2 minutes and then aspirated. The cells are then washed 2 timeswith PBS and 30 ml of complete DMEM added to each flask. The cells arethen allowed to incubate over night. The next day the cells areharvested by trypsinization and reseeded as needed depending upon thetype of assay to be performed.

A typical protocol for liposomal-mediated transfection as applied to CHOcells is described as follows; Cells to be used for transfection aresplit 24 hours prior to the transfection to provide flasks which are70-80% confluent at the time of transfection. A total of 10 Fg of DNAwhich may include varying ratios of receptor DNA plus any additional DNAneeded (e.g. G_(α) protein expression vector, reporter construct,antibiotic resistance marker, mock vector, etc.) is used to transfecteach 75 cm² flask of cells. Liposomal mediated transfection is carriedout according to the manufacturer=s recommendations (LipofectAMINE,GibcoBRL, Bethesda, Md.). Transfected cells are harvested 24 hours posttransfection and used or reseeded according the requirements of theassay to be employed.

A typical protocol for the electroporation method as applied to Cos-7cells is described as follows; Cells to be used for transfection aresplit 24 hours prior to the transfection to provide flasks which aresubconfluent at the time of transfection. The cells are harvested bytrypsinization resuspended in their growth media and counted. 4×10⁶cells are suspended in 360 Fl of DMEM and placed into an electroporationcuvette. 8 Fg of receptor DNA plus 8 Fg of any additional DNA needed(e.g. G_(α) protein expression vector, reporter construct, antibioticresistance marker, mock vector, etc.) is added to the cell suspension,the cuvette is placed into a BioRad Gene Pulser and subjected to anelectrical pulse (Gene Pulser settings: 0.25 kV voltage, 950 FFcapacitance). Following the pulse, 800 Fl of complete DMEM is added toeach cuvette and the suspension transferred to a sterile tube.

Complete medium is added to each tube to bring the final cellconcentration to 1×10⁵ cells/100 Fl. The cells are then plated as neededdepending upon the type of assay to be performed.

A typical protocol for viral mediated expression of heterologousproteins is described as follows for baculovirus infection of insect Sf9cells. The coding region of DNA encoding the receptor disclosed hereinmay be subcloned into pBlueBacIII into existing restriction sites orsites engineered into sequences 5′ and 3′ to the coding region of thepolypeptides. To generate baculovirus, 0.5 Fg of viral DNA (BaculoGold)and 3 Fg of DNA construct encoding a polypeptide may be co-transfectedinto 2×10⁶ Spodoptera frugiperda insect Sf9 cells by the calciumphosphate co-precipitation method, as outlined in by Pharmingen (in“Baculovirus Expression Vector System: Procedures and Methods Manual”).The cells then are incubated for 5 days at 27° C. The supernatant of theco-transfection plate may be collected by centrifugation and therecombinant virus plaque purified. The procedure to infect cells withvirus, to prepare stocks of virus and to titer the virus stocks are asdescribed in Pharmingen=s manual. Similar principals would in generalapply to mammalian cell expression via retro-viruses, Simliki forestvirus and double stranded DNA viruses such as adeno-, herpes-, andvacinia-viruses, and the like.

Stable Expression

Heterologous DNA can be stably incorporated into host cells, causing thecell to perpetually express a foreign protein. Methods for the deliveryof the DNA into the cell are similar to those described above fortransient expression but require the co-transfection of an ancillarygene to confer drug resistance on the targeted host cell. The ensuingdrug resistance can be exploited to select and maintain cells that havetaken up the heterologous DNA. An assortment of resistance genes areavailable including but not restricted to Neomycin, Kanamycin, andHygromycin. For the purposes of receptor studies, stable expression of aheterologous receptor protein is carried out in, but not necessarilyrestricted to, mammalian cells including, CHO, HEK293, LM(tk-), etc.

Cell Membrane Preparation

For binding assays, pellets of transfected cells are suspended inice-cold buffer (20 mM Tris.HCl, 5 mM EDTA, pH 7.4) and homogenized bysonication for 7 sec. The cell lysates are centrifuged at 200×g for 5min at 4° C. The supernatants are then centrifuged at 40,000×g for 20min at 4° C. The resulting pellets are washed once in the homogenizationbuffer and suspended in binding buffer (see methods for radioligandbinding). Protein concentrations are determined by the method ofBradford (1976) using bovine serum albumin as the standard. Bindingassays are usually performed immediately, however it is possible toprepare membranes in batch and store frozen in liquid nitrogen forfuture use.

Radioligand Binding Assays

Radioligand binding assays for the rat MCH1 receptor were carried outusing plasmid pcDNA3.1-rMCH1-f (ATCC Patent Deposit Designation No.PTA-3505). Plasmid pcDNA3.1-rMCH1-f comprises the regulatory elementsnecessary for expression of DNA in a mammalian cell operatively linkedto DNA encoding the rat MCH1 receptor so as to permit expressionthereof. Plasmid pcDNA3.1-rMCH1-f was deposited on Jul. 5, 2001, withthe American Type Culture Collection (ATCC), 12301 Parklawn Drive,Rockville, Maryland 20852, U.S.A. under the provisions of the BudapestTreaty for the International Recognition of the Deposit ofMicroorganisms for the Purposes of Patent Procedure and was accordedATCC Patent Deposit Designation No. PTA-3505.

Binding assays can also be performed as described hereinafter usingplasmid pEXJ.HR-TL231 (ATCC Accession No. 203197) Plasmid pEXJ.HR-TL231encodes the human MCH1 receptor and was deposited on Sep. 17, 1998, withthe American Type Culture Collection (ATCC), 12301 Parklawn Drive,Rockville, Md. 20852, U.S.A. under the provisions of the Budapest Treatyfor the International Recognition of the Deposit of Microorganisms forthe Purposes of Patent Procedure and was accorded ATCC Accession No.203197.

Human embryonic kidney Peak rapid 293 cells (Peakr293 cells) weretransiently transfected with DNA encoding the MCH1 receptor utilizingthe calcium phosphate method and cell membranes were prepared asdescribed above. Binding experiments with membranes from Peakr293 cellstransfected with the rat MCH1 receptor were performed with 0.08 nM[³H]Compound A (custom labeled by Amersham) (the synthesis of Compound Ais described in detail below) using an incubation buffer consisting of50 mM Tris pH 7.4, 10 mM MgCl₂, 0.16 mM PMSF, 1 mM 1,10 phenantrolineand 0.2% BSA. Binding was performed at 25° C. for 90 minutes.Incubations were terminated by rapid vacuum filtration over GF/C glassfiber filters, presoaked in 5% PEI using 50 nM Tris pH 7.4 as washbuffer. In all experiments, nonspecific binding is defined using 10 FMCompound A.

Functional Assays

Cells may be screened for the presence of endogenous mammalian receptorusing functional assays. Cells with no or a low level of endogenousreceptor present may be transfected with the exogenous receptor for usein functional assays.

A wide spectrum of assays can be employed to screen for receptoractivation. These range from traditional measurements of phosphatidylinositol, CAMP, Ca⁺⁺, and K⁺, for example; to systems measuring thesesame second messengers but which have been modified or adapted to behigher throughput, more generic, and more sensitive; to cell basedplatforms reporting more general cellular events resulting from receptoractivation such as metabolic changes, differentiation, and celldivision/proliferation, for example; to high level organism assays whichmonitor complex physiological or behavioral changes thought to beinvolved with receptor activation including cardiovascular, analgesic,orexigenic, anxiolytic, and sedation effects, for example.

Radioligand Binding Assay Results

The compounds described above were assayed using cloned rat MCH1. Thebinding affinities of the compounds are shown in Table I.

V. Synthesis of Compound A

Described below is the synthesis of Compound A. Compound A is theradiolabeled compound that was used in the radioligand binding assaysdescribed above.

N-[3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL]ACETAMIDE

The reaction of saturated of aqueous Na₂CO₃ solution (25 mL), tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acetamidophenyl boronic acid(30 mmol) and tetrakis-triphenylphosphine palladium (0) (1.15 g) indimethoxyethane (40 mL) at reflux temperature overnight gave tert-butyl4-[3-(acetylamino)phenyl]-3,6-dihydro-1 (2H)-pyridinecarboxylate.Deprotection of the BOC group using HCl in dioxane followed bybasification (pH 11-12) gave the desired product.

TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE

was prepared from 3-bromopropylamine hydrobromide and BOC₂₀ in thepresence of base in dichloromethane.

N-{3-1-(3-AMINOPROPYL)-1,2,3,6-TETRAHYDRO-4-PYRIDINYL]PHENYL}ACETAMIDE

The reaction of tert-butyl N-(3-bromopropyl)carbamate andN-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide in refluxingdioxane with catalytic Bu₄NI and base as described in Scheme A gavetert-butyl3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate.

Deprotection of the BOC group using HCl in dioxane followed bybasification (pH 11-12) gave the desired product.

METHYL(4S)-3-({[3-(4-[3-(ACETYLAMINO)PHENYL]-3,6-DIHYDRO-1(2H)-PYRIDINYL)PROPYL]AMINO}CARBONYL)-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE

Prepared from the reaction of 5-methyl 1-(4-nitrophenyl)(6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate(describe in PCT Publication No. WO 00/37026, published Jun. 29, 2000)andN-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamide:¹H NMR δ 8.90 (t, 1H, J=3.6 Hz), 7.75 (s, 1H), 7.50-7.00 (m, 8H), 6.68(s, 1H), 6.03 (br s, 1H), 4.67 (s, 2H), 3.71 (s, 3H), 3.47 (s, 3H), 3.38(ABm, 2H), 3.16 (m, 2H), 2.71 (t, 2H, J=5.4 Hz), 2.56 (m, 4H), 2.35-1.90(br, 2H), 2.17 (s, 3H), 1.82 (p, 2H, J=7.2 Hz); ESMS, 612.25. (M+H)⁺.

TRITIATED METHYL(4S)-3-{[(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE

Methyl(4S)-3-({[3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propyl]amino}carbonyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate was tritiated (Amersham) using the described cold method(H₂, balloon method, Methanol, Pd/C, overnight) to give the tritiatedmethyl(4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate((+)-isomer), which in turn, was used as a radioligand in the MCHpharmacological assays. TABLE I Example Ki No. Structure (nM) 1

79.6 2

197 3

1104 4

353 5

476 6

438 7

142 8

181 9

313 10

20.9 11

46.6 12

33.8VI. In-Vivo Methods

The following in vivo methods are performed to predict the efficacy ofMCH1 antagonists for the treatment of obesity (3-day body weight andsweetened condensed milk), depression (forced swim test), anxiety(social interaction test), and urinary disorders (DIRC and CSTI).

Effects of MCH1 Antagonists on Body Weight (3 Day)

Male Long Evans rats (Charles River) weighing 180-200 grams are housedin groups of four on a 12 hour light/dark cycle with free access to foodand water. Test compounds are administered twice daily via i.p.injection, 1 hour before the dark cycle and 2 hours after lights on, forthree days. All rats are weighed daily after each morning injection.Overall results are expressed as body weight (grams) gained per day(mean±SEM) and are analyzed by two-way ANOVA. Data for each time pointare analyzed by one-way ANOVA followed by post hoc Newman-Keuls test.The data are analyzed using the GraphPad Prism (v2.01) (GraphPadSoftware, Inc., San Diego, Calif.). All data are presented asmeans±S.E.M.

Effects of MCH1 Antagonists on Consumption of Sweetened Condensed Milk

Male C57BL/6 mice (Charles River) weighing 17-19 grams at the start ofexperiments are housed in groups of four or five on a 12 hour light/darkcycle with free access to food and water. For 7 days, mice are weighed,placed in individual cages and allowed to drink sweetened condensed milk(Nestle, diluted 1:3 with water) for 1 hour, 2-4 hours into the lightcycle. The amount of milk consumed is determined by weighing the milkbottle before and after each drinking bout. On the test day, micereceived i.p. injections of Test Compound (3, 10 or 30 mg/kg in 0.01%lactic acid), vehicle (0.01% lactic acid) of d-fenfluramine (10 mg/kg in0.01% lactic acid) 30 min. prior to exposure to milk. The amount of milkconsumed on the test day (in mls milk/kg body weight) is compared to thebaseline consumption for each mouse determined on the previous 2 days.Data for each time point are analyzed by one-way ANOVA.

Forced Swim Test (FST) in the Rat

Animals

Male Sprague-Dawley rats (Taconic Farms, N.Y.) are used in allexperiments. Rats are housed 5 per cage and maintained on a 12:12-hlight-dark cycle. Rats are handled for 1 minutes each day for 4 daysprior to behavioral testing.

Drug Administration

Animals are randomly assigned to receive a single i.p. administration ofvehicle (2.5% EtOH/2.5% Tween-80), imipramine (positive control; 60mg/kg), or Test Compound 60 minutes before the start of the 5 minutetest period. All injections are given using 1 cc tuberculin syringe with26⅜ gauge needles (Becton-Dickinson, VWR Scientific, Bridgeport, N.J.).The volume of injection is 1 ml/kg.

Experimental Design

The procedure used in this study is similar to that previously described(Porsolt, et al., 1978), except the water depth is 31 cm in thisprocedure. The greater depth in this test prevents the rats fromsupporting themselves by touching the bottom of the cylinder with theirfeet.

Swim sessions are conducted by placing rats in individual plexiglasscylinders (46 cm tall×20 cm in diameter) containing 23-25° C. water 31cm deep. Swim tests are conducted always between 900 and 1700 hours andconsisted of an initial 15-min conditioning test followed 24 h later bya 5-minute test. Drug treatments are administered 60 minutes before the5-minute test period. Following all swim sessions, rats are removed fromthe cylinders, dried with paper towels and placed in a heated cage for15 minutes and returned to their home cages. All test sessions arevideotaped using a color video camera and recorded for scoring later.

Behavioral Scoring

The rat's behavior is rated at 5 second intervals during the 5 minutetest by a single individual, who is blind to the treatment condition.Scored behaviors are:

-   -   1. Immobility—rat remains floating in the water without        struggling and is only making those movements necessary to keep        its head above water;    -   2. Climbing—rat is making active movements with its forepaws in        and out of the water, usually directed against the walls;    -   3. Swimming—rat is making active swimming motions, more than        necessary to merely maintain its head above water, e.g. moving        around in the cylinder; and    -   4. Diving—entire body of the rat is submerged.        Data Analysis

The forced swim test data (immobility, swimming, climbing, diving) aresubjected to a randomized, one-way ANOVA and post hoc tests conductedusing the Newman-Keuls test. The data are analyzed using the GprahPadPrism (v2.01) (GraphPad Software, Inc., San Diego, Calif.). All data arepresented as means±S.E.M. All data are presented as means±S.E.M.

Forced Swim Test (FST) in the Mouse

Animals

DBA/2 mice (Taconic Farms, N.Y.) are used in all experiments. Animalsare housed 5 per cage in a controlled environment under a 12:12 hourlight:dark cycle. Animals are handled 1 min each day for 4 days prior tothe experiment. This procedure included a mock gavage with a 1.5 inchfeeding tube.

Drug Administration

Animals are randomly assigned to receive a single administration ofvehicle (5% EtOH/5% Tween-80), Test Compound, or imipramine (60 mg/kg)by oral gavage 1 hour before the swim test.

Experimental Design

The procedure for the forced swim test in the mouse is similar to thatdescribed above for the rat, with some modifications. The cylinder usedfor the test is a 1 liter beaker (10.5 cm diameter×15 cm height) fill to800 ml (10 cm depth) of 23-25° C. water. Only one 5-minute swim test isconducted for each mouse, between 1300 and 1700 hours. Drug treatmentsare administered 30-60 minutes before the 5-minute test period.Following all swim sessions, mice are removed from the cylinders, driedwith paper towels and placed in a heated cage for 15 minutes. All testsessions are videotaped using a Sony color video camera and recorder forscoring later.

Behavorial Scoring

The behavior during minutes 2-5 of the test is played back on a TVmonitor and scored by the investigator. The total time spent immobile(animal floating with only minimal movements to remain afloat) andmobile (swimming and movements beyond those required to remain afloat)are recorded.

Data Analysis

The forced swim test data (time exhibiting immobility, mobility;seconds) are subjected to a randomized, one-way ANOVA and post hoc testsconducted using the Newman-Keuls test. The data are analyzed using theGraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.). Alldata are presented as means±S.E.M.

Social Interaction Test (SIT)

Rats are allowed to acclimate to the animal care facility for 5 days andare housed singly for 5 days prior to testing. Animals are handled for 5minutes per day. The design and procedure for the Social InteractionTest is carried out as previously described by Kennett, et al. (1997).On the test day, weight matched pairs of rats (±5%), unfamiliar to eachother, are given identical treatments and returned to their home cages.Animals are randomly divided into 5 treatment groups, with 5 pairs pergroup, and are given one of the following i.p. treatments: Test Compound(10, 30 or 100 mg/kg), vehicle (1 ml/kg) or chlordiazepoxide (5 mg/kg).Dosing is 1 hour prior to testing. Rats are subsequently placed in awhite perspex test box or arena (54×37×26 cm), whose floor is divided upinto 24 equal squares, for 15 minutes. An air conditioner is used togenerate background noise and to keep the room at approximately 74° F.All sessions are videotaped using a JVC camcorder (model GR-SZ1, ElmwoodPark, N.J.) with either TDK (HG ultimate brand) or Sony 30 minutevideocassettes. All sessions are conducted between 1300-1630 hours.Active social interaction, defined as grooming, sniffing, biting,boxing, wrestling, following and crawling over or under, is scored usinga stopwatch (Sportsline model no. 226, 1/100 sec. discriminability). Thenumber of episodes of rearing (animal completely raises up its body onits hind limbs), grooming (licking, biting, scratching of body), andface ishing (i.e. hands are moved repeatedly over face), and number ofsquares crossed are scored. Passive social interaction (animals arelying beside or on top of each other) is not scored. All behaviors areassessed later by an observer who is blind as to the treatment of eachpair. At the end of each test, the box is thoroughly wiped withmoistened paper towels.

Animals

Male albino Sprague-Dawley rats (Taconic Farms, N.Y.) are housed inpairs under a 12 hr light dark cycle (lights on at 0700 hrs.) with freeaccess to food and water.

Drug Administration

Test Compound is dissolved in 100% DMSO or 5% lactic acid, v/v (SigmaChemical Co., St. Louis, Mo.). Chlordiazepoxide (Sigma Chemical Co., St.Louis, Mo.) is dissolved in double distilled water. The vehicle consistsof 50% DMSO (v/v) or 100% dimethylacetamide (DMA). All drug solutionsare made up 10 minutes prior to injection and the solutions arediscarded at the end of the test day. The volume of drug solutionadministered is 1 ml/kg.

Data Analysis

The social interaction data (time interacting, rearing and squarescrossed) are subjected to a randomized, one-way ANOVA and post hoc testsconducted using the Student-Newman-Keuls test. The data are subjected toa test of normality (Shapiro-Wilk test). The data are analyzed using theGBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring,Md., 1997). All data are presented as means ∀ S.E.M.

In Vivo Models of the Micturition Reflex

The effects of compounds on the micturition reflex are assessed in the“distension-induced rhythmic contraction” (DIRC), as described inprevious publications (e.g. Maggi et al, 1987; Morikawa et al, 1992),and Continuous Slow Transvesicular Infusion (CSTI) models in rats.

DIRC Model

Female Sprague Dawley rats weighing approximately 300 g are anesthetizedwith subcutaneous urethane (1.2 g/kg).

The trachea is cannulated with PE240 tubing to provide a clear airwaythroughout the experiment. A midline abdominal incision is made and theleft and right ureters are isolated. The ureters are ligated distally(to prevent escape of fluids from the bladder) and cannulated proximallywith PE10 tubing. The incision is closed using 4-0 silk sutures, leavingthe PE10 lines routed to the exterior for the elimination of urine. Thebladder is canulated via the transurethral route using PE50 tubinginserted 2.5 cm beyond the urethral opening. This cannula is secured tothe tail using tape and connected to a pressure transducer. To preventleakage from the bladder, the cannula is tied tightly to the exteriorurethral opening using 4-0 silk.

To initiate the micturition reflex, the bladder is first emptied byapplying pressure to the lower abdomen, and then filled with normalsaline in 100 increments (maximum=2 ml) until spontaneous bladdercontractions occurred (typically 20-40 mmHg at a rate of one contractionevery 2 to 3 minutes. Once a regular rhythm is established, vehicle(saline) or Test Compounds are administered i.v. or i.p. to exploretheir effects on bladder activity. The 5-HT_(1A) antagonist WAY-100635is given as a positive control. Data are expressed as contractioninterval (in seconds) before drug application (basal), or after theapplication of vehicle or test article.

Continuous Slow Transvesicular Infusion (CSTI) Rat Model

Male Sprague Dawley rats weighing approximately 300 g are used for thestudy. Rats are anaesthetized with pentobarbitone sodium (50 mg/kg,i.p). Through a median abdominal incision, bladder is exposed and apolyethylene cannula (PE 50) is introduced into the bladder through asmall cut on the dome of the bladder and the cannula is secured with apurse string suture. The other end of the cannula is exteriorizedsubcutaneously at the dorsal neck area. Similarly, another cannula (PE50) is introduced into the stomach through a paramedian abdominalincision with the free end exteriorized subcutaneously to the neckregion. The surgical wounds are closed with silk 4-0 suture and theanimal is allowed to recover with appropriate post surgical care. On thefollowing day, the animal is placed in a rat restrainer. The open end ofthe bladder-cannula is connected to a pressure transducer as well asinfusion pump through a three-way stopcock. The bladder voiding cyclesare initiated by continuous infusion of normal saline at the rate of 100μl/min. The repetitive voiding contractions are recorded on a Power Labon-line data acquisition software. After an recording the basal voidingpattern for an hour, the test drug or vehicle is administered directlyinto stomach through the intragastric catheter and the voiding cyclesare monitored for 5 hours. Micturition pressure and frequency arecalculated before and after the treatment (at every 30 min interval) foreach animal. Bladder capacity is calculated from the frequency, based onthe constant infusion of 100 ul/min micturition. The effect of the testdrug is expressed as a percentage of basal, pre-drug bladder capacity.WAY 100635 is used as positive control for comparison.

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1. A compound having the structure:

wherein each A is independently —H, —F, —Cl, —Br, —I, —CN, —NO₂, —OR₃ orstraight chained or branched C₁-C₇ alkyl; wherein each B isindependently N or CH; wherein Z is CO or SO₂; wherein each R isindependently —H, —F or straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl; wherein R₄ is independently —OR₃,—NHR₃, —SR₃, —COR₃, straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the arylor heteroaryl is optionally substituted with one or more —F, —Cl, —Br,—I, —OR₂, or straight chained or branched C₁-C₇ alkyl; wherein each R₃is independently —H; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl or polyfluoroalkyl; aryl or heteroaryl, wherein the arylor heteroaryl is optionally substituted with one or more —F, —Cl, —Br,—I, —NO₂, —CN, —OR₂, or —NHR₂; wherein each R₂ is independently —H,straight chained or branched C₁-C₇ alkyl, aryl or heteroaryl, whereinthe aryl or heteroaryl is optionally substituted with one or more —F,—Cl, —Br, —I, —NO₂, —CN; and wherein n is an integer from 1 to 6inclusive; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1 wherein the compound has the structure:

wherein A, B, Z, n and R₄ are as defined in claim
 1. 3. The compound ofclaim 2 wherein the compound has the structure:

wherein A and Z are as defined in claim 1; wherein R₄ is aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith one or more —F, —Cl, —Br, —I, —OR₃, or straight chained or branchedC₁-C₇ alkyl; wherein each R₃ is straight chained or branched C₁-C₇alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN, or —OR₂;wherein each R₂ is —H, straight chained or branched C₁-C₇ alkyl, aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith one or more —F, —Cl, —Br, —I, —NO₂, —CN; and wherein n is asdefined in claim
 1. 4. The compound of claim 3 wherein the compound hasthe structure:

wherein A is as defined in claim 1; wherein R₂ is —H, straight chainedor branched C₁-C₇ alkyl, or aryl wherein the aryl is optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, or —CN; and whereinn is as defined in claim
 1. 5. The compound of claim 4 wherein thecompound has the structure:

wherein A is as defined in claim 1; wherein R₂ is straight chained orbranched C₁-C₇ alkyl; and wherein n is an integer from 3-6 inclusive. 6.The compound of claim 5 wherein the compound has the structure:

wherein each A is independently —H, —F, —Cl, —Br or —I; and R₂ is asdefined as in claim
 5. 7. The compound of claim 6 wherein the compoundhas the structure:

wherein each A is independently —H, —F or —Cl; and wherein R₂ isstraight chained or branched C₁-C₃ alkyl.
 8. The compound of claim 7wherein the compound has the structure:


9. The compound of claim 7 wherein the compound has the structure:


10. The compound of claim 2 wherein the compound has the structure:

wherein A is as defined in claim 1; and wherein R₂ is aryl, wherein thearyl is optionally substituted with one or more —F, —Cl, —Br, —I, —NO₂,or —CN; and wherein n is an integer from 1 to 6 inclusive;
 11. Thecompound of claim 10 wherein the compound has the structure:

wherein each A is independently —H, —F, —Cl, —Br or —I; and wherein R₂is as defined in claim
 10. 12. The compound of claim 11 wherein thecompound has the structure:

wherein each A is independently —H, —F or —Cl; and wherein R₂ is aryloptionally substituted with one or more —F, —Cl, or —Br.
 13. Thecompound of claim 12 wherein the compound has the structure:

wherein each A is independently —H, —F or —Cl; and wherein R₂ is aryloptionally substituted with one or more —F.
 14. The compound of claim 13wherein the compound has the structure:


15. The compound of claim 2 wherein the compound has the structure:

wherein A, Z, n and R₄ are as defined in claim
 1. 16. The compound ofclaim 15 wherein the compound has the structure:

wherein A is as defined in claim 1; and wherein R₄ is aryl optionallysubstituted with one or more —F, —Cl, —Br, —I, —OR₃, or straight chainedor branched C₁-C₇ alkyl; wherein each R₃ is idependently straightchained or branched C₁-C₇ alkyl, aryl or heteroaryl, wherein the aryl orheteroaryl is optionally substituted with one or more —F, —Cl, —Br, —I,—NO₂, —CN, or —OR₂; wherein each R₂ is independently straight chained orbranched C₁-C₇ alkyl; and wherein n is as defined in claim
 1. 17. Thecompound of claim 2 wherein the compound has the structure:

wherein A is as defined in claim 1; wherein Z is as defined in claim 1;wherein R₄ is independently —OR₃, —NHR₃, —COR₃ or —SR₃; wherein each R₃is independently straight chained or branched C₁-C₇ alkyl, aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith one or more —F, —Cl, —Br, —I, —NO₂, —CN, —OR₂, or —NHR₂; wherein R₂is —H, straight chained or branched C₁-C₇ alkyl, or aryl wherein thearyl is optionally substituted with one or more —F, —Cl, —Br, —I, —NO₂,—CN; and wherein n is an integer from 1 to 6 inclusive;
 18. The compoundof claim 17 wherein the compound has the structure:

wherein Z is as defined in claim 1; wherein each A is independently —H,—F, —Cl, —Br or —I; wherein R₄ is independently —OR₃, —NHR₃, or —COR₃;wherein R₃ is aryl optionally substituted with one or more —F, —Cl, —Br,—I, —NO₂, —CN, —OR₂ or —NHR₂; wherein each R₂ is independently —H,straight chained or branched C₁-C₇ alkyl or aryl optionally substitutedwith one or more —F, —Cl, —Br, —I, —NO₂, —CN; and wherein n is aninteger from 1 to 6 inclusive.
 19. The compound of claim 18 wherein thecompound has the structure:

wherein each A is independently —H or —F; wherein R₃ is aryl optionallysubstituted with one or more —F, —Cl, —Br, —I, —NO₂, —CN, —OR₂ or —NHR₂;wherein R₂ is independently straight chained or branched C₁-C₇ alkyl oraryl optionally substituted with one or more —F, —Cl, —Br or —I; andwherein n is an integer from 1 to 6 inclusive.
 20. The compound of claim17 wherein the compound has the structure:

wherein A is —H, —F, —Cl, —Br or —I; wherein R₃ is aryl optionallysubstituted with —NHR₂; and wherein R₂ is aryl optionally substitutedwith one or more —F, —Cl, —Br, —I;
 21. The compound of claim 20 whereinthe compound has the structure:


22. The compound of claim 18 wherein the compound has the structure:


23. The compound of claim 18 wherein the compound has the structure:

wherein A is —H, —F, —Cl, —Br or —I; wherein R₃ is aryl optionallysubstituted with one or more —F, —Cl, —Br or —I.
 24. The compound ofclaim 23 wherein the compound has the structure:


25. The compound of claim 23 wherein the compound has the structure:


26. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 27. A pharmaceutical compositionmade by admixing a compound of claim 1 and a pharmaceutically acceptablecarrier.
 28. A process for making a pharmaceutical compositioncomprising admixing a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 29. A method of treating a subject suffering from adisorder mediated by the MCH1 receptor comprising administering to asubject a therapeutically effective amount of a compound of claim
 1. 30.The method of claim 29, wherein the therapeutically effective amount isan amount between about 0.03 and about 300 mg.
 31. The method of claim30, wherein the disorder is depression.
 32. The method of claim 30,wherein the disorder is anxiety.
 33. The method of claim 30, wherein thedisorder is obesity.
 34. The method of claim 30, wherein the disorder isurge incontinence.
 35. A method of treating a subject suffering fromdepression, anxiety, urinary incontinence or obesity comprisingadministering to a subject a therapeutically effective amount of acompound of claim
 1. 36. The method of claim 35, wherein thetherapeutically effective amount is between about 0.03 and about 300 mg.37. The method of claim 35, wherein the subject suffers from depression.38. The method of claim 35, wherein the subject suffers from anxiety.39. The method of claim 35, wherein the subject suffers from obesity.40. A method of claim 35, wherein the subject suffers from is urgeincontinence.